ES2452039T3 - Salts of bicyclo-substituted pyrazolone azole derivatives, preparation procedure and use thereof - Google Patents

Salts of bicyclo-substituted pyrazolone azole derivatives, preparation procedure and use thereof Download PDF

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ES2452039T3
ES2452039T3 ES10785650.2T ES10785650T ES2452039T3 ES 2452039 T3 ES2452039 T3 ES 2452039T3 ES 10785650 T ES10785650 T ES 10785650T ES 2452039 T3 ES2452039 T3 ES 2452039T3
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salt
acid
phenyl
hydroxy
methyl
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Peng Cho Tang
Hejun LÜ
Hongbo Fei
Yiqian Chen
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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Abstract

Sales farmacéuticamente aceptables de un compuesto que tiene fórmula (I): en la que: Het se selecciona entre el grupo que consiste en fenilo, furilo y tienilo; cada uno de R1, R2, R3 y R4 se selecciona independientemente entre el grupo que consiste en hidrógeno y alquilo; n es 0, 1 ó 2; y las sales son sales de adición de bases que se seleccionan entre el grupo que consiste en sal sódica, sal de litio, sal potásica, sal cálcica, sal de magnesio, sal de arginina, sal de lisina, sal de metanamina, sal de dimetilamina, sal de trimetilamina, sal de etilamina, sal de dietilamina, sal de trietilamina, sal de etanolamina, sal de piperazina, sal de dibencil etilendiamina, sal de meglumina, sal de trometamina, sal de tetrametil amonio cuaternario, sal de tetraetil amonio cuaternario y sal colina.Pharmaceutically acceptable salts of a compound having formula (I): in which: Het is selected from the group consisting of phenyl, furyl and thienyl; each of R1, R2, R3 and R4 is independently selected from the group consisting of hydrogen and alkyl; n is 0, 1 or 2; and the salts are base addition salts that are selected from the group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, methanamine salt, dimethylamine salt , trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzyl ethylenediamine salt, meglumine salt, tromethamine salt, quaternary ammonium tetramethyl salt, quaternary tetraethyl ammonium salt and salt hill

Description

Sales de derivados azoicos de pirazolona biciclo-sustituidos, procedimiento de preparacion y uso de los mismos. Azoic salts of bicyclo-substituted pyrazolone derivatives, preparation process and use thereof.

CAMPO COUNTRYSIDE

Esta divulgacion se refiere a sales farmaceuticamente aceptables de nuevos derivados azoicos de pirazolona biciclosustituidos, procedimientos para su preparacion, composiciones farmaceuticas que contienen los mismos, y su uso como un agente terapeutico, particularmente como mimeticos de trombopoyetina (TPO) y agonistas del receptor de trombopoyetina. This disclosure refers to pharmaceutically acceptable salts of new bicyclic substituted pyrazolone azo derivatives, procedures for their preparation, pharmaceutical compositions containing them, and their use as a therapeutic agent, particularly as thrombopoietin (TPO) mimetics and thrombopoietin receptor agonists .

ANTECEDENTES BACKGROUND

La trombopoyetina (TPO), tambien denominada factor de crecimiento y desarrollo de megacariocitos (MGDF), factor estimulante de la trombocitopoyesis (TSF), ligando de leucemia c-mieloproliferativa (c-Mpl), ligando mpl, o megapoyetina, es una glicoproteina que se ha indicado para regular la produccion de plaquetas. Veanse Wendling, Thrombopoietin (TPO), also called megakaryocyte growth and development factor (MGDF), thrombocytopoiesis stimulating factor (TSF), c-myeloproliferative leukemia ligand (c-Mpl), mpl ligand, or megapoietin, is a glycoprotein that It has been indicated to regulate platelet production. See Wendling,

F. y col., Biotherapy 10(4): 269-77 (1998); Kuter D.J. y col., The Oncologist, 1: 98-106 (1996); Metcalf, Nature 369: 519-520 (1994). Bajo ciertas circunstancias, la actividad de la TPO es resultado de la union de la TPO con el receptor de TPO (tambien denominado Mpl). El receptor de TPO se ha clonado y su secuencia aminoacidica se ha descrito. Vease Vigon y col., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992). F. et al., Biotherapy 10 (4): 269-77 (1998); Kuter D.J. et al., The Oncologist, 1: 98-106 (1996); Metcalf, Nature 369: 519-520 (1994).   Under certain circumstances, the activity of the TPO is the result of the union of the TPO with the TPO receptor (also called Mpl). The TPO receptor has been cloned and its amino acid sequence has been described. See Vigon et al., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992).

La TPO es un polipeptido glicosilado de 332 aminoacidos que desempefa una funcion clave en la regulacion de la megacariocitopoyesis, y en el proceso en el que las plaquetas se producen por megacariocitos de medula osea. Veanse Kuter y col., Proc. Nat. Acad. Sci. USA 91: 11104-11108 (1994); Barley y col., Cell 77: 1117-1124 (1994); Kaushansky y col., Nature 369: 568-571 (1994); Wendling y col., Nature 369: 571-574 (1994); y Sauvage y col., Nature 369: 533-538 (1994). La TPO se produce en el higado pero funciona principalmente en la medula osea, donde estimula la diferenciacion de las celulas madre en los progenitores de megacariocitos, y estimula la proliferacion de megacariocitos, la poliploidizacion y, en ultima instancia, entra en las plaquetas en circulacion del cuerpo. La TPO es tambien un regulador primario en situaciones que implican trombocitopenia y en una serie de estudios que incluyen recuentos plaquetarios crecientes, el tamafo plaquetario y la incorporacion de isotopos en plaquetas de animales receptores. Vease, Metcalf Nature 369: 519-520 (1994). Especificamente, se considera que la TPO afecta a la megacariocitopoyesis de varias formas: (1) provoca un aumento del tamafo y numero de megacariocitos; (2) aumenta el contenido de ADN, las formas de poliploidia, y el numero de megacariocitos; (3) aumenta la endomitosis de megacariocitos; (4) aumenta el numero de megacariocitos maduros; (5) aumenta el porcentaje de celulas precursoras, el numero de celulas positivas pequefas de acetilcolinasterasa, el numero de celulas de medula osea. Las plaquetas son necesarias para la coagulacion de la sangre. Cuando el recuento de plaquetas es muy bajo, el paciente esta en riesgo de muerte por hemorragia catastrofica. Por lo tanto, la TPO se ha usado tanto para el diagnostico como para el tratamiento de diversos trastornos hematologicos, por ejemplo, enfermedades causadas principalmente por defectos plaquetarios. De forma analoga, La TPO puede ser util para el tratamiento de afecciones trombocitopenicas, especialmente las derivadas de la quimioterapia, radioterapia, o trasplante de medula para el tratamiento de cancer o linfoma. La lenta recuperacion de los niveles de plaquetas en los pacientes que padecen trombocitopenia es un problema grave. Es deseable proporcionar un compuesto para el tratamiento de la trombocitopenia que actue como un mimetico de TPO. Estos peptidos se disefaron para unir y activar el receptor de TPO (TPO-R) pero no tienen ninguna homologia de secuencia con la TPO natural. En los ultimos afos, se ha informado de una serie de mimeticos de TPO activos de moleculas pequefas, que incluyen derivados de poliaminas ciclicas (documento WO 00/28987), tiazol-2-il-benzamidas (documentos WO 01/07423, WO 01/53267), derivados azo-arilo (documentos WO 00/35446, WO 01/17349), 2-aril-naftimidazoles (documentos WO 01/39773, WO 01/53267), y derivados de semicarbazona (documento WO 01/34585). En sistemas basados en celulas, cada una de estas moleculas puede activar rutas de transduccion de sefales que dependen de la presencia del receptor de TPO en la membrana celular. Ciertos tipos de compuestos pueden actuar directamente sobre el propio receptor de TPO. Se descubrio que algunos de los compuestos mas preferidos de esta serie estimulan la proliferacion y diferenciacion de las lineas celulares humanas sensibles a TPO y la TPO en cultivos de medula osea humana que tiene una concentracion por debajo de 100 nM. Varias patentes cedidas a GlaxoSmithKline describieron un analogo de trombopoyetina, eltrombopag (documentos WO 2003/098992, WO 01 089457), con buena actividad. La presente divulgacion proporciona una serie de sales farmaceuticamente aceptables de derivados azoicos de pirazolona biciclo-sustituidos, que son mimeticos de TPO y agonistas del receptor de TPO mas eficaces. TPO is a glycosylated polypeptide of 332 amino acids that plays a key role in the regulation of megakaryocytopoiesis, and in the process in which platelets are produced by bone marrow megakaryocytes. See Kuter et al., Proc. Nat. Acad. Sci. USA 91: 11104-11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al., Nature 369: 571-574 (1994); and Sauvage et al., Nature 369: 533-538 (1994). TPO is produced in the liver but works primarily in the bone marrow, where it stimulates the differentiation of stem cells in megakaryocyte progenitors, and stimulates the proliferation of megakaryocytes, polyploidization and, ultimately, enters the circulating platelets of the body. TPO is also a primary regulator in situations involving thrombocytopenia and in a series of studies that include increasing platelet counts, platelet size and the incorporation of isotopes in platelets of recipient animals. See, Metcalf Nature 369: 519-520 (1994). Specifically, TPO is considered to affect megakaryocytopoiesis in several ways: (1) it causes an increase in the size and number of megakaryocytes; (2) increases the DNA content, the forms of polyploidy, and the number of megakaryocytes; (3) increases the endomitosis of megakaryocytes; (4) increases the number of mature megakaryocytes; (5) increases the percentage of precursor cells, the number of small positive acetylcholinesterase cells, the number of bone marrow cells. Platelets are necessary for blood clotting. When the platelet count is very low, the patient is at risk of death from catastrophic bleeding. Therefore, TPO has been used both for the diagnosis and for the treatment of various hematological disorders, for example, diseases caused mainly by platelet defects. Analogously, TPO may be useful for the treatment of thrombocytopenic conditions, especially those derived from chemotherapy, radiotherapy, or bone marrow transplantation for the treatment of cancer or lymphoma. The slow recovery of platelet levels in patients suffering from thrombocytopenia is a serious problem. It is desirable to provide a compound for the treatment of thrombocytopenia that acts as a TPO mimetic. These peptides were designed to bind and activate the TPO receptor (TPO-R) but have no sequence homology with natural TPO. In recent years, a number of active small molecule TPO mimetics have been reported, including cyclic polyamine derivatives (WO 00/28987), thiazol-2-yl-benzamides (WO 01/07423, WO 01 / 53267), azo-aryl derivatives (WO 00/35446, WO 01/17349), 2-aryl-naphthimidazoles (WO 01/39773, WO 01/53267), and semicarbazone derivatives (WO 01/34585) . In cell-based systems, each of these molecules can activate signal transduction pathways that depend on the presence of the TPO receptor in the cell membrane. Certain types of compounds can act directly on the TPO receptor itself. It was found that some of the most preferred compounds in this series stimulate the proliferation and differentiation of human cell lines sensitive to TPO and TPO in human bone marrow cultures that have a concentration below 100 nM. Several patents assigned to GlaxoSmithKline described a thrombopoietin analogue, eltrombopag (WO 2003/098992, WO 01 089457), with good activity. The present disclosure provides a series of pharmaceutically acceptable salts of bicyclo-substituted pyrazolone azole derivatives, which are TPO mimetics and more effective TPO receptor agonists.

La solicitud internacional N° PCT/CN2009/000001 presentada por el Solicitante de la presente invencion el 4 de enero de 2009 describio derivados azoicos de pirazolona biciclo-sustituidos novedosos y su uso como mimeticos de trombopoyetina (TPO) y agonistas del receptor de trombopoyetina. Los seis ejemplos (Ejemplo 1, Ejemplo 9, Ejemplo 15, Ejemplo 28, Ejemplo 43 y Ejemplo 52) descritos en la solicitud internacional proporcionaron los International application No. PCT / CN2009 / 000001 filed by the Applicant of the present invention on January 4, 2009 described novel bicyclo-substituted pyrazolone azo derivatives and their use as thrombopoietin (TPO) mimetics and thrombopoietin receptor agonists. The six examples (Example 1, Example 9, Example 15, Example 28, Example 43 and Example 52) described in the international application provided the

5 compuestos respectivamente como se indica a continuacion: 5 compounds respectively as indicated below:

acido 2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3-carboxilico, acido 5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-furan-2-carboxilico, acido 5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -biphenyl-3- acid carboxylic acid, 5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -phenyl } -furan-2-carboxylic acid, 5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino}

10 fenil)-furan-2-carboxilico, acido 4-(2-hidroxi-3-[N'-(3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno)hidrazino]bifenil-furan-2-carboxilico, acido 5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2-hidroxi-fenil)-furan-2carboxilico, 10 phenyl) -furan-2-carboxylic acid, 4- (2-hydroxy-3- [N '- (3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-) il) -1,5-dihydro-pyrazol-4-ylidene) hydrazino] biphenyl-furan-2-carboxylic acid, 5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl ) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic acid,

15 acido 4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-tiofeno-2-carboxilico, y los esteres de los mismos. 4- {2-Hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -phenyl} acid -thiophene-2-carboxylic acid, and the esters thereof.

Estos compuestos se ensayaron para mostrar una buena actividad como agonistas del receptor de TPO. Sin embargo, la solicitud internacional N° PCT/CN2009/000001 no describio las sales farmaceuticamente aceptables de 20 los compuestos. These compounds were tested to show good activity as TPO receptor agonists. However, international application No. PCT / CN2009 / 000001 did not describe the pharmaceutically acceptable salts of the compounds.

El inventor de la divulgacion descubrio que la forma de acido libre de los derivados azoicos de pirazolona biciclosustituidos era escasamente soluble en disolventes convencionales y, por lo tanto, desventajosa para prepararse en una forma de dosificacion medicinal, limitando su biodisponibilidad in vivo. Es necesario desarrollar nuevas formas The inventor of the disclosure found that the free acid form of the bicyclosubstituted pyrazolone azole derivatives was sparingly soluble in conventional solvents and, therefore, disadvantageous to be prepared in a medicinal dosage form, limiting its bioavailability in vivo. It is necessary to develop new ways

25 de derivados azoicos de pirazolona biciclo-sustituidos para mejorar su solubilidad y absorcion farmacocinetica, que pueden usarse en la preparacion convencional de formas de dosificacion. 25 of bicyclo-substituted pyrazolone azo derivatives to improve their solubility and pharmacokinetic absorption, which can be used in the conventional preparation of dosage forms.

RESUMEN SUMMARY

30 Con el fin de superar la insuficiencia de la tecnica anterior, la presente invencion proporciona sales farmaceuticamente aceptables de nuevos derivados azoicos de pirazolona biciclo-sustituidos, procedimientos para su preparacion, composiciones farmaceuticas que contienen los mismos, y su uso como agente terapeutico, particularmente como mimeticos de trombopoyetina (TPO) y agonistas del receptor de trombopoyetina. Las sales tienen buena actividad para tratar la trombocitopenia, una mejor solubilidad, buena actividad in vivo, mejor In order to overcome the insufficiency of the prior art, the present invention provides pharmaceutically acceptable salts of new bicyclo-substituted pyrazolone azo derivatives, methods for their preparation, pharmaceutical compositions containing them, and their use as a therapeutic agent, particularly as thrombopoietin (TPO) mimetics and thrombopoietin receptor agonists. The salts have good activity to treat thrombocytopenia, better solubility, good activity in vivo, better

35 biodisponibilidad, menor toxicidad y son un buen candidato en la preparacion de un medicamento para el tratamiento de la trombocitopenia. 35 bioavailability, lower toxicity and are a good candidate in the preparation of a drug for the treatment of thrombocytopenia.

"Los compuestos de la presente divulgacion" y "las sales de la presente divulgacion" son intercambiables, ambas de las cuales son las sales farmaceuticamente aceptables de derivados azoicos de pirazolona biciclo-sustituidos como 40 se especifica en la reivindicacion 1 y se representa por la formula (I). "The compounds of the present disclosure" and "the salts of the present disclosure" are interchangeable, both of which are pharmaceutically acceptable salts of bicyclo-substituted pyrazolone azo derivatives as specified in claim 1 and represented by the formula (I).

en la que: in which:

Het se selecciona entre el grupo que consiste en fenilo, furilo y tienilo; cada uno de R1, R2, R3 y R4 se selecciona independientemente entre el grupo que consiste en hidrogeno y alquilo; n es 0, 1 o 2; Het is selected from the group consisting of phenyl, furyl and thienyl; each of R1, R2, R3 and R4 is independently selected from the group consisting of hydrogen and I rent; n is 0, 1 or 2;

las sales son sales de adicion de bases que se seleccionan entre el grupo que consiste en sal sodica, sal de litio, sal potasica, sal calcica, sal de magnesio, sal de arginina, sal de lisina, sal de metanamina, sal de dimetilamina, sal de trimetilamina, sal de etilamina, sal de dietilamina, sal de trietilamina, sal de etanolamina, sal de piperazina, sal de dibencil etilendiamina, sal de meglumina, sal de trometamina, sal de the salts are base addition salts that are selected from the group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, methanamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzyl ethylenediamine salt, meglumine salt, tromethamine salt, salt

5 tetrametil amonio cuaternario, sal de tetraetil amonio cuaternario y sal colina. 5 quaternary tetramethyl ammonium, quaternary tetraethyl ammonium salt and choline salt.

La expresion "acido libre" se refiere a derivados azoicos de pirazolona biciclo-sustituidos que tienen la formula (I). The term "free acid" refers to azoic derivatives of bicyclo-substituted pyrazolone having the formula (I).

El equivalente se refiere a los tautomeros de los compuestos que tienen la formula (I), que se conoce bien el experto The equivalent refers to the tautomers of the compounds having the formula (I), which is well known to the expert

10 en la tecnica. Los tautomeros de los compuestos que tienen la formula (I) incluyen la siguiente formula (II) y la formula (III), pero sin limitacion: 10 in the technique. Tautomers of the compounds having formula (I) include the following formula (II) and formula (III), but without limitation:

15 Todos los tautomeros de los compuestos que tienen la formula (I) se incluyen en el alcance de la presente divulgacion y cada uno de ellos se incluye en la definicion de los compuestos que tienen la formula (I). All tautomers of the compounds having the formula (I) are included in the scope of the present disclosure and each of them is included in the definition of the compounds having the formula (I).

La expresion "sal farmaceuticamente aceptable" en la presente divulgacion se refiere a sales de adicion de bases farmaceuticamente no toxicas. Las sales son las formadas entre los compuestos que tienen la formula (I) y bases 20 apropiadas, tales como hidroxido de metales alcalinos, aminoacido basico, amina o amonio cuaternario, incluyendo sal sodica, sal de litio, sal potasica, sal calcica, sal de magnesio, sal de arginina, sal de lisina, sal de metanamina, sal de dimetilamina, sal de trimetilamina, sal de etilamina, sal de dietilamina, sal de trietilamina, sal de etanolamina, sal de piperazina, sal de dibencil etilendiamina, sal de meglumina, sal de trometamina, sal de tetrametil amonio cuaternario, sal de tetraetil amonio cuaternario y sal colina, preferiblemente sal de dietilamina, sal de etanolamina, The term "pharmaceutically acceptable salt" in the present disclosure refers to pharmaceutically non-toxic base addition salts. The salts are those formed between the compounds having the formula (I) and appropriate bases, such as alkali metal hydroxide, basic amino acid, amine or quaternary ammonium, including sodium salt, lithium salt, potassium salt, calcium salt, salt magnesium, arginine salt, lysine salt, methanamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzyl ethylenediamine salt, salt meglumine, tromethamine salt, tetramethyl ammonium quaternary salt, tetraethyl ammonium salt quaternary and choline salt, preferably diethylamine salt, ethanolamine salt,

25 sal colina, sal de piperazina, sal de meglumina y sal de trometamina, mas preferiblemente sal de etanolamina, sal colina, sal de meglumina y sal de trometamina, y mucho mas preferiblemente sal de etanolamina. Choline salt, piperazine salt, meglumine salt and tromethamine salt, more preferably ethanolamine salt, choline salt, meglumine salt and tromethamine salt, and much more preferably ethanolamine salt.

Las sales farmaceuticamente aceptables de los compuestos que tienen la formula (I) de la presente divulgacion preferiblemente incluyen, pero sin limitacion: 30 Pharmaceutically acceptable salts of the compounds having the formula (I) of the present disclosure preferably include, but are not limited to:

Ejemplo N° Example No.
Estructura Compuesto Structure Compound

1 one
bis-(etanolamina) del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]bifenil-3-carboxilico bis- (ethanolamine) of the acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] biphenyl-3-carboxylic

2 2
bis-(dietilamina) del acido (Z)-2'-hidroxi-3'-[N'-(-indan-5-il-3metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil3-carboxilico bis- (diethylamine) of the acid (Z) -2'-hydroxy-3 '- [N' - (- indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) - hydrazino] -biphenyl3-carboxylic

3 3
bis-(piperazina) del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]bifenil-3-carboxilico bis- (piperazine) of the acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] biphenyl-3-carboxylic

4 4
bis-(etanolamina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetilindan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]hidrazino}-2-hidroxi-fenil)-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethylindan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazole -4-ylidene] hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic

5 5
bis-(dietilamina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}2-hidroxi-fenil)-furan-2-carboxilico bis- (diethylamine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazole -4-ylidene] -hydrazino} 2-hydroxy-phenyl) -furan-2-carboxylic

6 6
bis-(piperazina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}2-hidroxi-fenil)-furan-2-carboxilico bis- (piperazine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazole -4-ylidene] -hydrazino} 2-hydroxy-phenyl) -furan-2-carboxylic

7 7
bis-(etanolamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

8 8
bis-(colina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (choline) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1 (5,6,7,8-tetrahydro-naphthalen-2-yl ) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

9 9
bis-(dietilamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (diethylamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

10 10
bis-(meglumina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (meglumine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

11 eleven
bis-(piperazina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (piperazine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

12 12
bis-(trometamol) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (trometamol) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

13 13
bis-(dibenciletilendiamina) del acido (Z)-5-(2-hidroxi-3-{N'[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2carboxilico bis- (dibenzylethylenediamine) of the acid (Z) -5- (2-hydroxy-3- {N '[3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl ) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

14 14
sal disodica del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico disodium salt of acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1, 5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

15 fifteen
bis-(L-arginina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (L-arginine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro-naphthalen-2- il) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

16 16
bis-(etanolamina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene ) -hydrazino] phenyl} -furan-2-carboxylic

17 17
bis-(dietilamina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-furan-2-carboxilico bis- (diethylamine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene ) -hydrazino] phenyl} -furan-2-carboxylic

18 18
bis-(piperazina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-furan-2-carboxilico bis- (piperazine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene ) -hydrazino] phenyl} -furan-2-carboxylic

19 19
bis-(etanolamina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-tiofeno-2-carboxilico bis- (ethanolamine) of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene ) -hydrazino] phenyl} -thiophene-2-carboxylic

20 twenty
bis-(dietilamina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-tiofeno-2-carboxilico bis- (diethylamine) of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene ) -hydrazino] phenyl} -thiophene-2-carboxylic

21 twenty-one
bis-(piperazina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-tiofeno-2-carboxilico bis- (piperazine) of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene ) -hydrazino] phenyl} -thiophene-2-carboxylic

22 22
bis-(etanolamina) del acido (Z)-4-(2-Hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftal-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -4- (2-Hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro-naphtal-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

23 2. 3
colina del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico Choline of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1 (5,6,7,8-tetrahydro-naphthalen-2-yl) -1, 5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

La presente divulgacion se refiere a un proceso para preparar las sales farmaceuticamente aceptables de compuestos que tienen la formula (I), que comprende las etapas de: The present disclosure relates to a process for preparing pharmaceutically acceptable salts of compounds having the formula (I), which comprises the steps of:

(a) (to)
disolver o suspender el acido libre de la presente divulgacion (el compuesto que tiene la formula (I)) en 7 dissolve or suspend the free acid of the present disclosure (the compound having the formula (I)) in 7

un disolvente organico, donde el disolvente organico se selecciona entre el grupo que consiste en metanol, etanol, acetona, acetato de etilo y tetrahidrofurano, preferiblemente tetrahidrofurano; an organic solvent, wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and tetrahydrofuran, preferably tetrahydrofuran;

(b) (b)
afadir una base a la mezcla con agitacion; donde la base puede ser una base organica o inorganica, tal como hidroxido de metal alcalino o hidroxido de metal alcalinoterreo, aminoacido basico, amina o amonio cuaternario; add a base to the mixture with stirring; where the base can be an organic or inorganic base, such as alkali metal hydroxide or alkaline earth metal hydroxide, basic amino acid, amine or quaternary ammonium;

(c)(C)
obtener las sales farmaceuticamente aceptables del compuesto que tiene la formula (1),  obtain the pharmaceutically acceptable salts of the compound having the formula (1),

donde las bases inorganicas incluyen hidroxidos de metales alcalinos que se seleccionan entre el grupo que consiste en el hidroxido sodico, hidroxido de litio, hidroxido potasico, hidroxido de calcio, hidroxido de magnesio; los aminoacidos basicos se seleccionan entre el grupo que consiste en lisina y arginina; las aminas se seleccionan entre el grupo que consiste en metanamina, dimetilamina, trimetilamina, etilamina, dietilamina, trietilamina, etanolamina, piperazina, dibencil etilendiamina, meglumina y trometamina; y los amonios cuaternarios se seleccionan entre el grupo que consiste en tetrametil amonio cuaternario, tetraetil amonio cuaternario, hidroxido de colina, preferiblemente dietilamina, etanolamina, hidroxido de colina, piperazina, meglumina y trometamina, mas preferiblemente etanolamina, hidroxido de colina, meglumina y trometamina, mucho mas preferiblemente etanolamina. where inorganic bases include alkali metal hydroxides that are selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; the basic amino acids are selected from the group consisting of lysine and arginine; the amines are selected from the group consisting of methanamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzyl ethylenediamine, meglumine and tromethamine; and quaternary ammoniums are selected from the group consisting of quaternary tetramethyl ammonium, quaternary tetraethyl ammonium, choline hydroxide, preferably diethylamine, ethanolamine, choline hydroxide, piperazine, meglumine and tromethamine, more preferably ethanolamine, choline hydroxide, meglumine and tromethamine , much more preferably ethanolamine.

En la etapa (b), la proporcion de equivalencia del acido libre y el hidroxido de metal alcalino, aminoacido basico, amina y amonio cuaternario era preferiblemente 1:5-5:1, mas preferiblemente 1:1-1:3, y mucho mas preferiblemente 1:1-1:2. In step (b), the equivalence ratio of free acid and alkali metal hydroxide, basic amino acid, amine and quaternary ammonium was preferably 1: 5-5: 1, more preferably 1: 1-1: 3, and much more preferably 1: 1-1: 2.

En la etapa (c), la separacion de sales preferiblemente incluia la filtracion directa de la mezcla de reaccion, la concentracion de la mezcla de reaccion y la recristalizacion en un disolvente organico. Las sales pueden secarse en la condicion tal como secado al vacio o secado al aire de alta temperatura. In step (c), the salt separation preferably included the direct filtration of the reaction mixture, the concentration of the reaction mixture and the recrystallization in an organic solvent. The salts may be dried under the condition such as vacuum drying or high temperature air drying.

Las reacciones de formacion de sales se realizaron generalmente en condiciones de refrigeracion, temperatura ambiente o calentamiento. Sin embargo, cabe mencionar que la temperatura de la reaccion esta relacionada con la formacion de sales, que se conoce bien por el experto en la tecnica. El intervalo de las temperaturas de reaccion de la presente divulgacion es de la temperatura ambiente al punto de ebullicion del disolvente de reaccion, preferiblemente 0-40 °C. El experto en la tecnica puede determinar facilmente la temperatura de reaccion mas preferible de las reacciones de formacion de sales mediante tecnicas convencionales. Salt formation reactions were generally performed under refrigeration, room temperature or heating conditions. However, it is worth mentioning that the reaction temperature is related to the formation of salts, which is well known to those skilled in the art. The range of reaction temperatures of the present disclosure is from room temperature to the boiling point of the reaction solvent, preferably 0-40 ° C. The person skilled in the art can easily determine the most preferable reaction temperature of salt formation reactions by conventional techniques.

La presente divulgacion se refiere al uso de las sales farmaceuticamente aceptables de los compuestos que tienen la formula (I) en la preparacion de un agonista del receptor de trombopoyetina. The present disclosure relates to the use of pharmaceutically acceptable salts of the compounds having the formula (I) in the preparation of a thrombopoietin receptor agonist.

La presente divulgacion se refiere al uso de las sales farmaceuticamente aceptables de los compuestos que tienen la formula (I) como se especifica en la reivindicacion 1 en la preparacion de un medicamento para el tratamiento de trombocitopenia, donde el medicamento se co-administra con un farmaco seleccionado entre el grupo que consiste en un factor estimulador de colonias, una citocina, una quimiocina, una interleucina o agonista o antagonista del receptor de citocina, un receptor soluble, un anticuerpo agonista o antagonista de receptor, o uno o mas peptidos o compuestos de moleculas pequefas que tienen el mismo mecanismo con el farmaco. The present disclosure relates to the use of pharmaceutically acceptable salts of the compounds having the formula (I) as specified in claim 1 in the preparation of a medicament for the treatment of thrombocytopenia, wherein the medicament is co-administered with a drug selected from the group consisting of a colony stimulating factor, a cytokine, a chemokine, an interleukin or agonist or antagonist of the cytokine receptor, a soluble receptor, an agonist antibody or receptor antagonist, or one or more peptides or compounds of small molecules that have the same mechanism with the drug.

La presente divulgacion se refiere a las sales farmaceuticamente aceptables de los compuestos que tienen la formula (I) como se especifica en la reivindicacion 1, para su uso como un medicamento para el tratamiento de trombocitopenia, donde el medicamento se co-administra con un farmaco seleccionado entre el grupo que consiste en un factor estimulador de colonias, una citocina, una quimiocina, una interleucina o agonista o antagonista del receptor de citocina, un receptor soluble, un anticuerpo agonista o antagonista de receptor, o uno o mas peptidos o compuestos de moleculas pequefas que tienen el mismo mecanismo con el farmaco, donde el medicamento esta en forma de forma de dosificacion oral, o el medicamento esta en forma de forma de dosificacion parenteral. The present disclosure relates to the pharmaceutically acceptable salts of the compounds having the formula (I) as specified in claim 1, for use as a medicament for the treatment of thrombocytopenia, wherein the medicament is co-administered with a drug. selected from the group consisting of a colony stimulating factor, a cytokine, a chemokine, an interleukin or cytokine receptor agonist or antagonist, a soluble receptor, an agonist antibody or receptor antagonist, or one or more peptides or compounds of Small molecules that have the same mechanism with the drug, where the medicine is in the form of an oral dosage form, or the medicine is in the form of a parenteral dosage form.

La presente divulgacion se refiere a composiciones farmaceuticas que comprenden una cantidad terapeuticamente eficaz de las sales farmaceuticamente aceptables de los compuestos que tienen la formula (I) como se especifica en la reivindicacion 1 y vehiculos o agentes diluyentes farmaceuticamente aceptables, donde la composicion se coadministra con un farmaco seleccionado entre el grupo que consiste en un factor estimulador de colonias, una citocina, una quimiocina, una interleucina y agonista del receptor de citocina. La presente divulgacion tambien se refiere al uso de las composiciones en la preparacion de un medicamento para el tratamiento de trombocitopenia, donde la co-administracion comprende usar los farmacos de la presente divulgacion al mismo tiempo o sucesivamente. The present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of the pharmaceutically acceptable salts of the compounds having the formula (I) as specified in claim 1 and pharmaceutically acceptable carriers or diluting agents, wherein the composition is co-administered with a drug selected from the group consisting of a colony stimulating factor, a cytokine, a chemokine, an interleukin and cytokine receptor agonist. The present disclosure also refers to the use of the compositions in the preparation of a medicament for the treatment of thrombocytopenia, where co-administration comprises using the drugs of the present disclosure at the same time or successively.

La presente divulgacion se refiere a un proceso para preparar las composiciones farmaceuticas que comprenden una cantidad terapeuticamente eficaz de las sales farmaceuticamente aceptables de los compuestos que tienen la formula (I) como se especifica en la reivindicacion 1 y vehiculos o agentes diluyentes farmaceuticamente aceptables, donde el proceso comprende la etapa de combinar los compuestos que tienen la formula (I) con vehiculos o agentes diluyentes farmaceuticamente aceptables. The present disclosure relates to a process for preparing pharmaceutical compositions comprising a therapeutically effective amount of the pharmaceutically acceptable salts of the compounds having the formula (I) as specified in claim 1 and pharmaceutically acceptable diluting vehicles or agents, wherein The process comprises the step of combining the compounds having the formula (I) with pharmaceutically acceptable diluting vehicles or agents.

En el proceso de preparacion de composiciones farmaceuticas, es importante preparar el farmaco de forma apropiada manejada y tratada de forma conveniente, no solo en vista a una preparacion disponible en el mercado, sino tambien en vista a una preparacion de la forma de dosificacion farmaceutica que contiene los compuestos activos. In the process of preparing pharmaceutical compositions, it is important to prepare the drug properly handled and treated conveniently, not only in view of a commercially available preparation, but also in view of a preparation of the pharmaceutical dosage form that It contains the active compounds.

En otro aspecto, es importante ofrecer una curva de concentracion en plasma de farmaco fiable, reproducible y constante despues de la administracion a un sujeto en el proceso de preparacion de composiciones farmaceuticas. In another aspect, it is important to offer a reliable, reproducible and constant drug plasma concentration curve after administration to a subject in the process of preparing pharmaceutical compositions.

Otros factores importantes incluyen durabilidad quimica, estabilidad en estado solido y tiempo de almacenamiento del principio activo. Los farmacos que contienen su composicion preferiblemente pueden almacenarse relativamente durante mucho tiempo si ningun cambio obvio en el caracter fisico y quimico de sus componentes activos, tales como composicion quimica, densidad, higroscopicidad y solubilidad. Other important factors include chemical durability, solid state stability and storage time of the active substance. The drugs containing their composition can preferably be stored relatively for a long time if no obvious change in the physical and chemical character of their active components, such as chemical composition, density, hygroscopicity and solubility.

Tambien es importante proporcionar un farmaco con una quimica lo mas pura posible. It is also important to provide a drug with a chemistry as pure as possible.

Tipicamente, un farmaco puede ofrecer las siguientes ventajas: tratamiento conveniente, preparacion de las formas de dosificacion del farmaco adecuadas y solubilidad fiable si el farmaco puede obtenerse en una forma estable, tal como una forma cristalina estable, que se conoce bien por el experto en la tecnica. Typically, a drug can offer the following advantages: convenient treatment, preparation of the appropriate drug dosage forms and reliable solubility if the drug can be obtained in a stable form, such as a stable crystalline form, which is well known to the person skilled in the art. The technique.

La cantidad eficaz del principio activo en una unidad de dosificacion farmaceutica como se ha descrito anteriormente sera no toxica, preferiblemente seleccionada entre el intervalo de 0,001-100 mg/kg de peso total, mas preferiblemente 0,001-50 mg/kg. Al tratar un sujeto que necesita un mimetico de TPO, la dosis seleccionada se administra preferiblemente por via oral o parenteral. Las formas parenterales preferidas incluyen formas de administracion topica, rectal, transdermica, inyeccion e infusion continua. Las unidades de dosificacion orales para administracion en seres humanos preferiblemente contienen de 0,05 a 3500 mg de principio activo, mucho mas preferiblemente de 0,5 a 1000 mg de principio activo. Se prefiere la administracion oral, que usa una dosificacion inferior. Sin embargo, tambien puede usarse la administracion parenteral, a dosis elevadas, cuando sea segura y conveniente para el paciente. Las dosificaciones anteriores se refieren a la cantidad preferida del principio activo expresada como el acido libre. The effective amount of the active ingredient in a pharmaceutical dosage unit as described above will be non-toxic, preferably selected from the range of 0.001-100 mg / kg of total weight, more preferably 0.001-50 mg / kg. When treating a subject that needs a TPO mimetic, the selected dose is preferably administered orally or parenterally. Preferred parenteral forms include topical, rectal, transdermal, injection and continuous infusion forms. Oral dosage units for administration in humans preferably contain from 0.05 to 3500 mg of active ingredient, much more preferably from 0.5 to 1000 mg of active ingredient. Oral administration is preferred, which uses a lower dosage. However, parenteral administration can also be used, at high doses, when it is safe and convenient for the patient. The above dosages refer to the preferred amount of the active ingredient expressed as the free acid.

Se entendera por un experto en la tecnica que la cantidad y separacion optima de las dosis individuales del principio activo dependera de la naturaleza y extension de la afeccion que se va a tratar, la forma, ruta y sitio de administracion, y el paciente particular que se va a tratar, y tales optimos pueden determinarse mediante tecnicas convencionales. Tambien se apreciara por un experto en la tecnica que el ciclo optimo de tratamiento, es decir, el numero de dosis del principio activo dadas por dia durante un numero definido de dias, puede determinarse por los expertos en la tecnica usando pruebas de determinacion del ciclo convencional de tratamiento. It will be understood by one skilled in the art that the quantity and optimal separation of the individual doses of the active ingredient will depend on the nature and extent of the condition to be treated, the form, route and site of administration, and the particular patient who it is going to be treated, and such optimum can be determined by conventional techniques. It will also be appreciated by one skilled in the art that the optimal treatment cycle, that is, the number of doses of the active ingredient given per day for a defined number of days, can be determined by those skilled in the art using cycle determination tests. Conventional treatment

Los compuestos de la presente divulgacion pueden administrarse por via oral o parenteral, donde los compuestos pueden prepararse en comprimidos, pildoras, polvos y granulos usados en diferentes rutas de administracion. En las formas de dosificacion solidas anteriores, los componentes activos se mezclan con al menos un tipo de diluyente inerte. De acuerdo con una operacion convencional, las formas de dosificacion orales tambien incluyen otra sustancia, tal como lubricantes, emolientes y antioxidantes ademas del diluyente inerte. Si se hacen en capsulas, comprimidos y pildoras, las formas de dosificacion contienen agentes tamponantes. Los comprimidos y pildoras pueden fabricarse en formas de dosificacion de liberacion sostenida. The compounds of the present disclosure can be administered orally or parenterally, where the compounds can be prepared in tablets, pills, powders and granules used in different routes of administration. In the above solid dosage forms, the active components are mixed with at least one type of inert diluent. According to a conventional operation, oral dosage forms also include another substance, such as lubricants, emollients and antioxidants in addition to the inert diluent. If they are made in capsules, tablets and pills, the dosage forms contain buffering agents. The tablets and pills can be manufactured in sustained release dosage forms.

Aunque pueden usarse emulsiones no acuosas, las formas de dosificacion parenterales de la presente divulgacion contienen una solucion acuosa esteril y estas formas de dosificacion tambien contienen adyuvantes, por ejemplo antisepticos, agentes humectantes, agentes penetrantes, agentes tamponantes, agentes emulsionantes y dispersantes. El proceso de esterilizacion puede usar un filtro de retencion de bacterias y se afaden agentes esterilizantes a las composiciones que se irradiaron o se calentaron para su esterilizacion. Although non-aqueous emulsions may be used, the parenteral dosage forms of the present disclosure contain a sterile aqueous solution and these dosage forms also contain adjuvants, for example antiseptics, wetting agents, penetrating agents, buffering agents, emulsifying and dispersing agents. The sterilization process can use a bacteria retention filter and sterilizing agents are added to the compositions that were irradiated or heated for sterilization.

En comparacion con los acidos libres, las sales de la presente divulgacion tienen las siguientes ventajas: In comparison with free acids, the salts of the present disclosure have the following advantages:

(1) (one)
Las sales de la presente divulgacion se disuelven facilmente en los disolventes convencionales, tales como agua, metanol, acido clorhidrico al 0,1% y se adaptan para preparar formas de dosificacion convencionales, donde la solubilidad de las sales de etanolamina se mejora en acido clorhidrico al 0,1%. The salts of the present disclosure readily dissolve in conventional solvents, such as water, methanol, 0.1% hydrochloric acid and are adapted to prepare conventional dosage forms, where the solubility of ethanolamine salts is improved in hydrochloric acid. at 0.1%.

(2)(2)
Las sales de la presente divulgacion tienen una mejor estabilidad.  The salts of the present disclosure have a better stability.

(3)(3)
Las sales de la presente divulgacion tienen una mejor actividad biologica in vitro.  The salts of the present disclosure have a better biological activity in vitro.

(4) (4)
Las sales de la presente divulgacion tienen mejores caracteristicas farmacocineticas in vivo, una mejor absorcion, mayor biodisponibilidad y mejor curva de farmacocinetica, donde la sal de etanolamina, sal colina, sal de piperazina, sal de meglumina y la sal de trometamina tienen mejores caracteristicas de la farmacocinetica, preferiblemente la sal de etanolamina. The salts of the present disclosure have better pharmacokinetic characteristics in vivo, better absorption, greater bioavailability and better pharmacokinetic curve, where ethanolamine salt, choline salt, piperazine salt, meglumine salt and tromethamine salt have better characteristics of the pharmacokinetics, preferably the ethanolamine salt.

(5) (5)
El proceso de preparacion de las sales de la presente divulgacion tiene la ventaja de tener un alto rendimiento, una alta pureza, ser rapido, como y de bajo coste, donde la sal de etanolamina, sal colina, sal de dietilamina y sal de piperazina son mas ventajosas en rutas del proceso, aquellas que pueden The process of preparing the salts of the present disclosure has the advantage of having a high yield, high purity, being fast, as well as low cost, where the ethanolamine salt, choline salt, diethylamine salt and piperazine salt are most advantageous in process routes, those that can

cristalizarse directamente. crystallize directly.

En comparacion con los acidos libres, las sales de la presente divulgacion tienen mejores caracteristicas de solubilidad, estabilidad, actividad biologica in vitro y farmacocinetica, preferiblemente sal de dietilamina, sal de etanolamina, sal colina, sal de piperazina, sal de meglumina y sal de trometamina, mas preferiblemente sal de etanolamina, sal colina, sal de meglumina y sal de trometamina, mucho mas preferiblemente sal de etanolamina. In comparison with free acids, the salts of the present disclosure have better characteristics of solubility, stability, in vitro and pharmacokinetic biological activity, preferably diethylamine salt, ethanolamine salt, choline salt, piperazine salt, meglumine salt and salt. tromethamine, more preferably ethanolamine salt, choline salt, meglumine salt and tromethamine salt, much more preferably ethanolamine salt.

DESCRIPCION DETALLADA DETAILED DESCRIPTION

A menos que se indique otra cosa, los siguientes terminos usados en la memoria descriptiva y las reivindicaciones tienen los significados que se describen a continuacion. Unless otherwise indicated, the following terms used in the specification and the claims have the meanings described below.

El termino "etanolamina" se refiere a "2-aminoetanol". The term "ethanolamine" refers to "2-aminoethanol."

El termino "colina" se refiere a "(2-hidroxietil)trimetilamina". The term "choline" refers to "(2-hydroxyethyl) trimethylamine".

El termino "meglumina" se refiere a "N-metil-D-meglumina". The term "meglumine" refers to "N-methyl-D-meglumine".

La expresion "composicion farmaceutica" se refiere a una mezcla de una o mas de las sales farmaceuticamente aceptables del compuesto descrito en el presente documento o profarmacos del mismo, con otros componentes quimicos, tales como vehiculos fisiologica/farmaceuticamente aceptables. El proposito de una composicion farmaceutica es facilitar la administracion de un compuesto a un organismo. The term "pharmaceutical composition" refers to a mixture of one or more of the pharmaceutically acceptable salts of the compound described herein or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

El termino "estabilidad" se refiere a estabilidad quimica y estabilidad solida. The term "stability" refers to chemical stability and solid stability.

La expresion "estabilidad quimica" se refiere al almacenamiento de los compuestos de la presente divulgacion, incluyendo formas aisladas o formas de dosificacion mezcladas con vehiculos o diluyentes farmaceuticamente aceptables (por ejemplo dosificacion oral, tal como comprimidos, capsulas y asi sucesivamente) en condiciones convencionales con una degradacion quimica o descomposicion quimica insignificante. The term "chemical stability" refers to the storage of the compounds of the present disclosure, including isolated forms or dosage forms mixed with pharmaceutically acceptable carriers or diluents (for example oral dosage, such as tablets, capsules and so on) under conventional conditions. with a chemical degradation or insignificant chemical decomposition.

La expresion "estabilidad solida" se refiere al almacenamiento de los compuestos de la presente divulgacion, incluyendo formas solidas aisladas o formas de dosificacion mezcladas con vehiculos o diluyentes farmaceuticamente aceptables en formas solidos (por ejemplo dosificacion oral, tal como comprimidos, capsulas y asi sucesivamente) en condiciones convencionales con una transformacion en estado solido insignificante (por ejemplo cristalizacion, recristalizacion, cambio de fase en estado solido, hidratacion, deshidratacion, solvatacion o eliminacion del disolvente). The term "solid stability" refers to the storage of the compounds of the present disclosure, including isolated solid forms or dosage forms mixed with pharmaceutically acceptable carriers or diluents in solid forms (for example oral dosage, such as tablets, capsules and so on ) under conventional conditions with insignificant solid state transformation (for example crystallization, recrystallization, phase change in solid state, hydration, dehydration, solvation or solvent removal).

Los ejemplos de la expresion "almacenado en condiciones convencionales" incluyen el intervalo de temperatura de 80 °C a +50 °C (preferiblemente de 0 °C a 40 °C, mas preferiblemente a temperatura ambiente, tal como 15 °C-30 °C), el intervalo de presion de 0,1 pa a 2 pa (preferiblemente atmosferica), el intervalo de humedad relativa del 5% al 95% (preferiblemente del 10%-60%) y/o expuesto a una luz UV/visible de 460 lux experimentando un tiempo mas prolongado (mas de o igual a seis meses). Examples of the expression "stored under conventional conditions" include the temperature range of 80 ° C to +50 ° C (preferably 0 ° C to 40 ° C, more preferably at room temperature, such as 15 ° C-30 ° C), the pressure range from 0.1 pa to 2 pa (preferably atmospheric), the relative humidity range from 5% to 95% (preferably 10% -60%) and / or exposed to UV / visible light of 460 lux experiencing a longer time (more than or equal to six months).

La expresion "administracion parenteral" incluye administracion intravenosa, intramuscular, subcutanea, intranasal, intra-rectal, intravaginal o intraperitoneal, preferiblemente administracion oral. The term "parenteral administration" includes intravenous, intramuscular, subcutaneous, intranasal, intra-rectal, intravaginal or intraperitoneal administration, preferably oral administration.

La expresion "higroscopicidad" farmaceutica se refiere al caracter de la capacidad o grado de la sustancia para poder absorber agua bajo cierta temperatura y humedad. Las muestras de prueba son ingredientes satisfechos con el Drug Quality Control Standard. Los envases de los farmacos y las condiciones de almacenamiento pueden remitirse a los resultados de la prueba anterior. The term "pharmaceutical hygroscopicity" refers to the character of the ability or grade of the substance to be able to absorb water under a certain temperature and humidity. Test samples are ingredients satisfied with the Drug Quality Control Standard. Drug containers and storage conditions can be referred to the results of the previous test.

PROCEDIMIENTO DE SiNTESIS DE LOS COMPUESTOS DESVELADOS SYNTHESIS PROCEDURE OF THE DEVELOPED COMPOUNDS

Con el fin de conseguir el fin de la divulgacion, la divulgacion emplea las siguientes soluciones tecnicas: In order to achieve the end of the disclosure, the disclosure employs the following technical solutions:

El procedimiento de sintesis del compuesto que tiene la formula (I) se refiere al ejemplo 1, ejemplo 9, ejemplo 15, ejemplo 28, ejemplo 43 y ejemplo 52 de la solicitud internacional N° PCT/CN2009/000001 presentada el 4 de enero de 2009. The synthesis procedure of the compound having the formula (I) refers to example 1, example 9, example 15, example 28, example 43 and example 52 of international application No. PCT / CN2009 / 000001 filed on January 4, 2009

El proceso para preparar las sales farmaceuticamente aceptables de los compuestos que tienen la formula (I) comprende las etapas de: The process for preparing the pharmaceutically acceptable salts of the compounds having the formula (I) comprises the steps of:

(a) (to)
disolver o suspender el acido libre de la presente divulgacion (el compuesto que tiene la formula (I)) en un disolvente organico, donde el disolvente organico se selecciona entre el grupo que consiste en metanol, etanol, acetona, acetato de etilo y tetrahidrofurano, preferiblemente tetrahidrofurano; dissolve or suspend the free acid of the present disclosure (the compound having the formula (I)) in an organic solvent, where the organic solvent is selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and tetrahydrofuran, preferably tetrahydrofuran;

(b) (b)
afadir una base a la mezcla con agitacion; donde la base puede ser una base organica o inorganica, tal como hidroxido de metal alcalino o hidroxido de metal alcalinoterreo, aminoacido basico, amina o amonio cuaternario; add a base to the mixture with stirring; where the base can be an organic or inorganic base, such as alkali metal hydroxide or alkaline earth metal hydroxide, basic amino acid, amine or quaternary ammonium;

(c)(C)
obtener las sales farmaceuticamente aceptables del compuesto que tiene la formula (I),  obtain the pharmaceutically acceptable salts of the compound having the formula (I),

donde las bases inorganicas incluyen hidroxidos de metales alcalinos que se seleccionan entre el grupo que consiste en el hidroxido sodico, hidroxido de litio, hidroxido potasico, hidroxido de calcio, hidroxido de magnesio; las aminas y los amonios cuaternarios se seleccionan entre el grupo que consiste en tetrametil amonio cuaternario, tetraetil amonio cuaternario, etanolamina, colina, lisina, arginina, metanamina, dimetilamina, trimetilamina, etilamina, dietilamina, trietilamina, dibencil etilendiamina, meglumina, piperazina y trometamina; preferiblemente dietilamina, etanolamina, piperazina, hidroxido de colina, meglumina y trometamina, mas preferiblemente etanolamina, hidroxido de colina, meglumina y trometamina, mucho mas preferiblemente etanolamina. where inorganic bases include alkali metal hydroxides that are selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; quaternary amines and ammoniums are selected from the group consisting of quaternary tetramethyl ammonium, quaternary tetraethyl ammonium, ethanolamine, choline, lysine, arginine, methanamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, dibenzyl ethylenediamine, meglumine, meglumine, pipeline ; preferably diethylamine, ethanolamine, piperazine, choline hydroxide, meglumine and tromethamine, more preferably ethanolamine, choline hydroxide, meglumine and tromethamine, much more preferably ethanolamine.

En la etapa (b), la proporcion de equivalencia del acido libre y la base era preferiblemente 1:5-5:1, mas preferiblemente 1:1-1:3, y mucho mas preferiblemente 1:1-1:2. In step (b), the equivalence ratio of the free acid and the base was preferably 1: 5-5: 1, more preferably 1: 1-1: 3, and much more preferably 1: 1-1: 2.

En la etapa (c), la separacion de sales preferiblemente incluia la filtracion directa de la mezcla de reaccion, la concentracion de la mezcla de reaccion y la recristalizacion en un disolvente organico. Las sales pueden secarse en la condicion tal como secado al vacio o secado al aire de alta temperatura. In step (c), the salt separation preferably included the direct filtration of the reaction mixture, the concentration of the reaction mixture and the recrystallization in an organic solvent. The salts may be dried under the condition such as vacuum drying or high temperature air drying.

Las reacciones de formacion de sales se realizan generalmente en condiciones de refrigeracion, temperatura ambiente o calentamiento. Sin embargo, cabe mencionar que la temperatura de la reaccion tiene influencia sobre la reaccion de formacion de sales, que se conoce bien por el experto en la tecnica. El intervalo de las temperaturas de reaccion de la presente divulgacion es de la temperatura ambiente al punto de ebullicion del disolvente de reaccion, preferiblemente 0-40 °C. El experto en la tecnica puede determinar facilmente la temperatura de reaccion mas preferible de las reacciones de formacion de sales mediante tecnicas convencionales. Salt formation reactions are generally carried out under refrigeration, room temperature or heating conditions. However, it should be mentioned that the reaction temperature has an influence on the salt formation reaction, which is well known to one skilled in the art. The range of reaction temperatures of the present disclosure is from room temperature to the boiling point of the reaction solvent, preferably 0-40 ° C. The person skilled in the art can easily determine the most preferable reaction temperature of salt formation reactions by conventional techniques.

La presente divulgacion se describe adicionalmente mediante los siguientes Ejemplos. The present disclosure is further described by the following Examples.

EJEMPLOS EXAMPLES

Las estructuras de todos los compuestos se identificaron por resonancia magnetica nuclear (1H RMN) o espectrometria de masas (EM). The structures of all the compounds were identified by nuclear magnetic resonance (1 H NMR) or mass spectrometry (MS).

La RMN se realizo en un espectrometro Bruker AVANCE-400. Los disolventes apropiados incluian metanol deuterado (CD3OD), cloroformo deuterado (CDCl3) y dimetilsulfoxido deuterado (DMSO-d6) con tetrametilsilano (TMS) como patron interno y los desplazamientos quimicos se registraron como ppm (10-6). The NMR was performed on a Bruker AVANCE-400 spectrometer. Appropriate solvents included deuterated methanol (CD3OD), deuterated chloroform (CDCl3) and deuterated dimethylsulfoxide (DMSO-d6) with tetramethylsilane (TMS) as internal standard and chemical shifts were recorded as ppm (10-6).

La EM se determino en un espectrometro de masas FINNIGAN LCQ Ad (IEN) (Thermo, Modelo: Finnigan LCQ advantage MAX). The MS was determined in a FINNIGAN LCQ Ad (IEN) mass spectrometer (Thermo, Model: Finnigan LCQ advantage MAX).

La EC50 se determino en un NovoStar ELIASA (BMG Co. Alemania). The EC50 was determined in a NovoStar ELIASA (BMG Co. Germany).

El gel de silice de capa fina se refiere a una placa de gel de silice Yantai Huanghai HSGF254 o Qingdao GF254. La dimension de las placas usadas en el analisis por TLC fue de 0,15 mm-0,2 mm, y la dimension de las placas usadas en la purificacion del producto fue de 0,4 mm-0,5 mm. The thin layer silica gel refers to a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The size of the plates used in the TLC analysis was 0.15 mm-0.2 mm, and the size of the plates used in the purification of the product was 0.4 mm-0.5 mm.

La cromatografia en columna uso generalmente gel de silice de malla 200-300 Yantai Huanghai como vehiculo. Column chromatography generally uses 200-300 Yantai Huanghai mesh silica gel as a vehicle.

El analisis por HPLC se determino en un espectrometro de cromatografia liquida de alto rendimiento Agilent 1200DAD (columna cromatografica Sunfire C18 150 x 4,6 mm) y un espectrometro de cromatografia liquida de alto rendimiento Waters 2695-2996 (columna cromatografica Gimini C18 150 x 4,6 mm). The HPLC analysis was determined on an Agilent 1200DAD high performance liquid chromatography spectrometer (Sunfire C18 150 x 4.6 mm chromatographic column) and a Waters 2695-2996 high performance liquid chromatography spectrometer (Gimini C18 150 x 4 chromatography column , 6 mm).

Las reacciones de hidrogenacion a presion se realizaron con un espectrometro de hidrogenacion Parr 3916EKX y un generador de hidrogeno QL. Las reacciones por microondas se realizaron con un reactor de microondas CEM Discover-S 908860. Pressure hydrogenation reactions were performed with a Parr 3916EKX hydrogenation spectrometer and a QL hydrogen generator. Microwave reactions were performed with a Discover-S 908860 CEM microwave reactor.

En las reacciones de hidrogenacion, el sistema de reaccion generalmente se dejo al vacio y se cargo con hidrogeno, y la operacion se repitio tres veces. In hydrogenation reactions, the reaction system was generally left in vacuo and charged with hydrogen, and the operation was repeated three times.

El material de partida conocido de la invencion puede prepararse mediante el procedimiento de sintesis convencional en la tecnica, o adquirirse en ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc o Dari chemical Company, etc. The known starting material of the invention can be prepared by the method of conventional synthesis in the art, or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.

A menos que se indique otra cosa, las siguientes reacciones se pusieron en una atmosfera de nitrogeno. Unless otherwise indicated, the following reactions were placed in a nitrogen atmosphere.

La expresion "atmosfera de nitrogeno" se refiere a que un matraz de reaccion esta equipado con un globo de nitrogeno de 1 l. The expression "nitrogen atmosphere" refers to the fact that a reaction flask is equipped with a 1 l nitrogen balloon.

La expresion "atmosfera de hidrogeno" se refiere a que un matraz de reaccion esta equipado con un globo de 5 hidrogeno de 1 l. The term "hydrogen atmosphere" refers to the fact that a reaction flask is equipped with a 1 l hydrogen balloon.

A menos que se indique otra cosa, la solucion usada en la siguiente reaccion se refiere a una solucion acuosa. Unless otherwise indicated, the solution used in the following reaction refers to an aqueous solution.

El termino "TLC" se refiere a cromatografia de capa fina. The term "TLC" refers to thin layer chromatography.

10 El termino "HPLC" se refiere a cromatografia liquida de alto rendimiento. Condiciones de ensayo por HPLC: tiempo de realizacion: 30 min, temperatura de la columna: 30 °C PDA: 230 nm, fase movil: acetonitrilo:agua (acido trifluoroacetico al 0,1%) = 25:75, caudal: 1,0 mU minuto. Columna cromatografica: C18, 150 x 4,6 mm Gemini. 10 The term "HPLC" refers to high performance liquid chromatography. HPLC test conditions: completion time: 30 min, column temperature: 30 ° C PDA: 230 nm, mobile phase: acetonitrile: water (0.1% trifluoroacetic acid) = 25:75, flow rate: 1, 0 mU minute Chromatographic column: C18, 150 x 4.6 mm Gemini.

15 Ejemplo 1: bis-(etanolamina) del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-bifenil-3-carboxilico Example 1: bis- (ethanolamine) of the acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene) hydrazino] -biphenyl-3-carboxylic

20 Etapa 1 20 Stage 1

2-Bromo-6-nitro-fenol 2-Bromo-6-nitro-phenol

25 Una solucion de 60 ml de acido sulfurico concentrado diluido con 186 ml de agua se enfrio a temperatura ambiente. A la solucion se le afadio nitrato sodico (79,2 g, 0,93 mol). Se afadio gota a gota 2-bromo-fenol 1a(60 ml, 0,52 mol) a tal velocidad que la temperatura de la reaccion se mantuvo por debajo de 25 °C. La mezcla de reaccion se agito a temperatura ambiente durante 2 horas. El precipitado se disolvio en 320 ml de acetato de etilo. La mezcla se lavo con agua y saturada salmuera, se seco sobre sulfato de magnesio anhidro, se filtro y el filtrado se concentro a A solution of 60 ml of concentrated sulfuric acid diluted with 186 ml of water was cooled to room temperature. Sodium nitrate (79.2 g, 0.93 mol) was added to the solution. 2-Bromo-phenol 1a (60 ml, 0.52 mol) was added dropwise at such a rate that the reaction temperature was maintained below 25 ° C. The reaction mixture was stirred at room temperature for 2 hours. The precipitate was dissolved in 320 ml of ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to

30 presion reducida. El residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo 2-bromo-6-nitro-fenol 1b (48,2 g, rendimiento del 42,8%) en forma de un solido de color amarillo. EM m/z (IEN): 218 [M+1]1H RMN (400 MHz, CDCl3): 8 11,18 (s, 1H), 8,12-8,15 (m, 1H), 7,89-7,91 (m, 1H), 6,88-7,02 (m, 1H) 30 reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain the title compound 2-bromo-6-nitro-phenol 1b (48.2 g, yield 42.8%) as a yellow solid . MS m / z (ESI): 218 [M + 1] 1H NMR (400 MHz, CDCl3): 8.11.18 (s, 1H), 8.12-8.15 (m, 1H), 7.89- 7.91 (m, 1H), 6.88-7.02 (m, 1H)

35 Etapa 2 35 Stage 2

1-Bromo-2-metoxi-3-nitro-benceno 1-Bromo-2-methoxy-3-nitro-benzene

40 Se disolvio 2-bromo-6-nitro-fenol 1b(46,55 g, 0,214 mol) en 500 ml de acetona seguido de la adicion de carbonato 40 2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 ml of acetone followed by the addition of carbonate

potasico (35,36 g, 0,26 mol) y yodometano (20,1 ml, 0,32 mol). La mezcla de reaccion se calento a reflujo a 70 °C durante 40 horas. La mezcla de reaccion se concentro a presion reducida y se diluyo con 1300 ml de acetato de etilo y 500 ml de agua. La fase acuosa se extrajo con acetato de etilo (300 ml x 2). Los extractos organicos combinados se lavaron con acido clorhidrico 4 M y una solucion saturada de bicarbonato sodico y despues se secaron sobre sulfato de magnesio anhidro, se filtraron y el filtrado se concentro a presion reducida. El residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo 1-bromo-2-metoxi-3-nitrobenceno 1c (44,59 g, rendimiento del 90,0%) en forma de un solido de color pardo. EM m/z (IEN): 234 [M+1] potassium (35.36 g, 0.26 mol) and iodomethane (20.1 ml, 0.32 mol). The reaction mixture was heated to reflux at 70 ° C for 40 hours The reaction mixture was concentrated under reduced pressure and diluted with 1300 ml of ethyl acetate. and 500 ml of water. The aqueous phase was extracted with ethyl acetate (300 ml x 2). The combined organic extracts they were washed with 4M hydrochloric acid and a saturated sodium bicarbonate solution and then dried over Anhydrous magnesium sulfate was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain the title compound 1-bromo-2-methoxy-3-nitrobenzene 1c (44.59 g, yield 90.0%) as a brown solid. MS m / z (ESI): 234 [M + 1]

Etapa 3 Stage 3

Acido 2'-metoxi-3'-nitro-bifenil-3-carboxilico 2'-Methoxy-3'-nitro-biphenyl-3-carboxylic acid

Se disolvieron 1-bromo-2-metoxi-3-nitro-benceno 1c (23,25 g, 0,10 mol), acido 3-carboxifenil-boronico (19,5 g, 117 mmol) y tetraquis(trifenilfosfina)paladio (8,86 g, 7,7 mol) en una mezcla de disolvente de 100 ml de una solucion 2 M de carbonato sodico y 500 ml de 1,4-dioxano. La mezcla de reaccion se calento a reflujo a 105 °C durante 43 horas. La mezcla se concentro a presion reducida y despues se afadieron 300 ml de acido clorhidrico 6 N y 400 ml de acetato de etilo. La fase acuosa se extrajo con acetato de etilo (200 ml x 2). Los extractos organicos combinados se secaron sobre sulfato de magnesio anhidro, se filtraron y el filtrado se concentro a presion reducida para obtener el compuesto del titulo acido 2'-metoxi-3'-nitro-bifenil-3-carboxilico 1d (53,93 g) en forma de un solido de color amarillo claro. EM m/z (IEN): 272 [M-1] 1H RMN (400 MHz, CDCl3): 8 8,11 (s, 1H), 8,02 (d, J = 8,0 Hz, 1H), 7,90-7,92 (m, 1H), 7,82-7,84 (m, 1H), 7,21-7,75 (m, 1H), 7,63-7,67 (m, 1H), 7,42-7,46 (m, 1H), 3,45 (s, 3H) 1-Bromo-2-methoxy-3-nitro-benzene 1c (23.25 g, 0.10 mol), 3-carboxyphenyl boronic acid (19.5 g, 117 were dissolved) mmol) and tetrakis (triphenylphosphine) palladium (8.86 g, 7.7 mol) in a 100 ml solvent mixture of a 2M solution of sodium carbonate and 500 ml of 1,4-dioxane. The reaction mixture was heated at reflux at 105 ° C for 43 hours. The mixture was concentrated under reduced pressure and then 300 ml of 6 N hydrochloric acid and 400 ml of ethyl acetate. The aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound 2'-methoxy-3'-nitro-biphenyl-3-carboxylic acid 1d (53.93 g) in the form of a yellow solid Sure. MS m / z (ESI): 272 [M-1] 1H NMR (400 MHz, CDCl3): 8 8.11 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.90-7.92 (m, 1H), 7, 82-7.84 (m, 1H), 7.21-7.75 (m, 1H), 7.63-7.67 (m, 1H), 7.42-7.46 (m, 1H), 3.45 (s, 3H)

Etapa 4 Stage 4

Acido 2'-metoxi-3'-amino-bifenil-3-carboxilico 2'-Methoxy-3'-amino-biphenyl-3-carboxylic acid

Se disolvio acido 2'-metoxi-3'-nitro-bifenil-3-carboxilico 1d (0,48 g, 1,74 mmol) en 60 ml de etanol seguido de la adicion de 0,5 g de paladio sobre carbono (10%) y formiato amonico (1,1 g, 17,4 mmol). La mezcla de reaccion se calento a reflujo a 80 °C durante 20 minutos. La mezcla se filtro y el filtrado se concentro a presion reducida y se seco para obtener el compuesto del titulo acido 2'-metoxi-3'-aminobifenil-3-carboxilico 1e (0,42 g, rendimiento del 93,3%) en forma de un solido de color blanco. EM m/z (IEN): 242 [M-1] 2'-Methoxy-3'-nitro-biphenyl-3-carboxylic acid 1d (0.48 g, 1.74 mmol) was dissolved in 60 ml of ethanol followed by the addition of 0.5 g of palladium on carbon (10%) and ammonium formate (1.1 g, 17.4 mmol). The reaction mixture is Heat at reflux at 80 ° C for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure and dry to obtain the title compound 2'-methoxy-3'-aminobiphenyl-3-carboxylic acid 1e (0.42 g, yield of 93.3%) in the form of a white solid. MS m / z (ESI): 242 [M-1]

Etapa 5 Stage 5

Bromhidrato del acido 3'-amino-2'-hidroxi-bifenil-3-carboxilico 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid hydrobromide

Empleo de un procedimiento conocido descrito en la solicitud de patente WO 01/89457: Se disolvio acido 2'-metoxi3'-amino-bifenil-3-carboxilico 1e (2,5 g, 10,3 mmol) en 100 ml de acido bromhidrico (40%). La mezcla de reaccion se calento a reflujo a 120 °C durante una noche. La mezcla se concentro a presion reducida y el residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo bromhidrato del acido 3'-amino-2'-hidroxi-bifenil-3-carboxilico 1f (2,4 g, 88,8%) en forma de un solido de color caqui. EM m/z (IEN): 230 [M+1] Use of a known procedure described in patent application WO 01/89457: 2'-Methoxy3'-amino-biphenyl-3-carboxylic acid 1e (2.5 g, 10.3 mmol) was dissolved in 100 ml of hydrobromic acid (40%) The reaction mixture is Heat at reflux at 120 ° C overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to obtain the title compound acid hydrobromide 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid 1f (2.4 g, 88.8%) in the form of a khaki solid. MS m / z (ESI): 230 [M + 1]

Etapa 6 Stage 6

Indan-5-il-hidrazina Indan-5-il-hydrazine

Se disolvio indan-5-ilamina 19 (3,59 g, 27,0 mmol) en 20 ml de acido clorhidrico concentrado tras la refrigeracion en un bafo de hielo-agua y la mezcla se agito durante 10 minutos. Se afadieron gota a gota 10 ml de una solucion de nitrito sodico (1,86 g, 27,0 mmol) y la mezcla se agito durante 15 minutos mas y se uso en la siguiente reaccion. Indan-5-ylamine 19 (3.59 g, 27.0 mmol) was dissolved in 20 ml of concentrated hydrochloric acid after cooling in an ice-water bafo and the mixture was stirred for 10 minutes. 10 ml of a solution of drops was added dropwise sodium nitrite (1.86 g, 27.0 mmol) and the mixture was stirred for a further 15 minutes and used in the next reaction.

Despues de la refrigeracion en un bafo de hielo-sal, se disolvio cloruro de estannoso dihidrato (24,4 g, 108,0 mmol) en 10 ml de acido clorhidrico concentrado seguido de la adicion de la mezcla auxiliar que se ha mencionado anteriormente. La mezcla de reaccion se calento hasta la temperatura ambiente y se hizo reaccionar durante 1,5 horas. Despues, la mezcla se ajusto a pH 9 con una solucion al 40% de hidroxido sodico tras la refrigeracion en un bafo de hielo-agua. La mezcla se extrajo con 400 ml de acetato de etilo y los extractos organicos combinados se concentraron a presion reducida y se secaron para obtener el compuesto del titulo indan-5-il-hidrazina 1h (2,05 g, rendimiento del 51,3%) en forma de un solido de color rojizo. EM m/z (IEN): 149 [M+1] After cooling in an ice-salt bath, stannous chloride dihydrate (24.4 g, 108.0 mmol) was dissolved in 10 ml of concentrated hydrochloric acid followed by the addition of the aforementioned auxiliary mixture previously. The reaction mixture was heated to room temperature and reacted for 1.5 hours. Then, the mixture was adjusted to pH 9 with a 40% solution of sodium hydroxide after cooling in a bafo of ice-water. The mixture was extracted with 400 ml of ethyl acetate and the combined organic extracts were concentrated under reduced pressure and dried to obtain the title compound indan-5-yl-hydrazine 1h (2.05 g, 51.3% yield) in the form of a reddish solid. MS m / z (ESI): 149 [M + 1]

Etapa 7 Stage 7

2-Indan-5-il-5-metil-2,4-dihidro-pirazol-3-ona 2-Indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one

Se disolvio indan-5-il-hidrazina 1h (2,05 g, 13,8 mmol) en 50 ml de acido acetico seguido de la adicion de acetoacetato de etilo (1,76 ml, 13,8 mmol). La mezcla de reaccion se calento a 100 °C durante una noche. La mezcla se concentro a presion reducida y el residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo 2-indan-5-il-5-metil-2,4-dihidro-pirazol-3-ona 1i (1,84 g, rendimiento del 62,3%) en forma de un solido de color amarillo. EM m/z (IEN): 215 [M+1] 1H RMN (400 MHz, CDCl3): 8 7,69 (s, 1H), 7,60 (d, J = 8,0 Hz, 1H), 7,24 (d, J = 8 Hz, 1H), 3,44 (s, 2H), 2,90 2,97 (m, 4H), 3,21 (s, 3H), 2,07 2,14 (m, 2H) Indan-5-yl-hydrazine 1h (2.05 g, 13.8 mmol) was dissolved in 50 ml of acetic acid followed by the addition of ethyl acetoacetate (1.76 ml, 13.8 mmol). The reaction mixture was heated at 100 ° C overnight. Mix it was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to obtain the title compound 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (1.84 g, 62.3% yield) in the form of a yellow solid. MS m / z (ESI): 215 [M + 1] 1 H NMR (400 MHz, CDCl 3): 8 7.69 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.24 (d, J = 8 Hz, 1 H), 3 , 44 (s, 2H), 2.90 2.97 (m, 4H), 3.21 (s, 3H), 2.07 2.14 (m, 2H)

Etapa 8 Stage 8

Acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3-carboxilico (Z) -2'-Hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] - biphenyl-3-carboxylic

Despues de la refrigeracion en un bafo de hielo-agua, se disolvio el bromhidrato del acido 3'-amino-2'-hidroxi-bifenil3-carboxilico 1f (267 mg, 1,16 mmol) en 10 ml de acido clorhidrico 1 M seguido de la adicion gota a gota de 10 ml de una solucion de nitrito sodico (88 mg, 1,28 mmol) y 2-indan-5-il-5-metil-2,4-dihidro-pirazol-3-ona 1i (249 mg, 1,16 mmol). La mezcla se ajusto a pH 8 con una solucion saturada de bicarbonato sodico seguido de la adicion de 10 ml de etanol. La mezcla de reaccion se calento hasta la temperatura ambiente durante una noche. La mezcla se filtro, se seco y se re-cristalizo en metanol para obtener el compuesto del titulo acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3metil-5-carbonil-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3-carboxilico 1j (60 mg, rendimiento del 11,4%) en forma de un solido de color amarillo. EM m/z (IEN): 453 [M-1]1H RMN (400 MHz, DMSO-d6): 8 13,76 (s a, 1H), 13,03 (s a, 1H), 9,66 (s a, 1H), 8,13 (s, 1H), 7,96-7,98 (d, J = 8,1 Hz, 1H), 7,60-7,82 (m, 5H), 7,28-7,30 (d, J = 8,1 Hz, 1H), 7,13-7,17 (m, 2H), 2,86-2,93 (m, 4H), 2,34 (s, 3H), 2,032,10 (m, 2H) After cooling in an ice-water bath, 3'-amino-2'-hydroxy-biphenyl3-carboxylic acid 1f hydrobromide (267 mg, 1.16 mmol) was dissolved in 10 ml of 1M hydrochloric acid followed of the dropwise addition of 10 ml of a solution of sodium nitrite (88 mg, 1.28 mmol) and 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i ( 249 mg, 1.16 mmol). The mixture was adjusted to pH 8 with a saturated sodium bicarbonate solution followed by the addition of 10 ml of ethanol. The reaction mixture was heated to room temperature overnight. The mixture was filtered, dried and re-crystallized from methanol to obtain the title compound acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3methyl-5- carbonyl-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -biphenyl-3-carboxylic acid 1j (60 mg, 11.4% yield) as a yellow solid. MS m / z (ESI): 453 [M-1] 1H NMR (400 MHz, DMSO-d6): 8 13.76 (sa, 1H), 13.03 (sa, 1H), 9.66 (sa, 1H), 8.13 (s, 1H), 7.96-7.98 (d, J = 8.1 Hz, 1H), 7.60-7.82 (m, 5H), 7.28-7 , 30 (d, J = 8.1 Hz, 1H), 7.13-7.17 (m, 2H), 2.86-2.93 (m, 4H), 2.34 (s, 3H), 2,032.10 (m, 2H)

Etapa 9 Stage 9

bis-(Etanolamina) del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]bifenil-3-carboxilico bis- (Ethanolamine) of the acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazole-4- ilidene) -hydrazino] biphenyl-3-carboxylic

Se disolvio el acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-carbonil-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil3-carboxilico 1j (454 mg, 1,0 mmol) en 16 ml de tetrahidrofurano. La mezcla de reaccion se afadio con etanolamina (143 mg, 2,35 mmol) y se agito durante 3 horas. La mezcla se filtro, la torta de filtro se lavo con tetrahidrofurano (2 ml x 3), y el producto solido se seco al vacio para obtener el compuesto del titulo bis-(etanolamina) del acido (Z)-2'hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-carbonil-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3-carboxilico 1 (553 mg, rendimiento: 96,0%) en forma de un solido de color rojo intenso. EM m/z (IEN): 453 [M-1]1H RMN (400 MHz, CD3OD): 8 8,13 (s, 1H), 7,92 (d, J = 7,6 Hz, 1H), 7,69 (m, 3H), 7,61 (d, J = 8,0 Hz, 1H), 7,45 (t, J = 7,6 Hz, 1H), 7,25 (d, J = 8,0 Hz, 1H), 7,17 (d, J = 8,0 Hz, 1H), 6,98 (t, J = 8,0 Hz, 1H), 3,65 (t, J = 5,2 Hz, 4H), 2,95 (m, 4H), 2,86 (t, J = 5,2 Hz, 4H), 2,41 (s, 3H),2,12 (m, 2H) The acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydro-pyrazol-4-ylidene) - hydrazino] -biphenyl3-carboxylic acid 1j (454 mg, 1.0 mmol) in 16 ml of tetrahydrofuran. The reaction mixture was added with ethanolamine (143 mg, 2.35 mmol) and stirred for 3 hours. The mixture was filtered, the filter cake was washed with tetrahydrofuran (2 ml x 3), and the solid product was dried in vacuo to obtain the title compound bis- (ethanolamine) of the acid (Z) -2'hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -biphenyl-3-carboxylic acid 1 (553 mg, yield : 96.0%) in the form of an intense red solid. MS m / z (ESI): 453 [M-1] 1H NMR (400 MHz, CD3OD): 8 8.13 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7 , 69 (m, 3H), 7.61 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 8, 0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 3.65 (t, J = 5.2 Hz , 4H), 2.95 (m, 4H), 2.86 (t, J = 5.2 Hz, 4H), 2.41 (s, 3H), 2.12 (m, 2H)

Ejemplo 2: bis-(dietilamina) del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-bifenil-3-carboxilico Example 2: bis- (diethylamine) of the acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazole -4-ylidene) hydrazino] -biphenyl-3-carboxylic

Se disolvio acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-carbonil-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3carboxilico 1j (150 mg, 0,33 mmol) en 5 ml de tetrahidrofurano para formar una solucion de color rojo intenso. La solucion se afadio gota a gota con dietilamina (48 mg, 0,66 mmol) para formar una solucion de color purpura y se agito durante 2 horas. El solido se precipito en la solucion. La mezcla se filtro, la torta de filtro se lavo con tetrahidrofurano (1 ml x 3), y el producto solido se seco al vacio para obtener el compuesto del titulo bis-(dietilamina) (Z) -2'-Hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydro-pyrazol-4-ylidene) -hydrazino acid was dissolved ] -biphenyl-3-carboxylic acid 1j (150 mg, 0.33 mmol) in 5 ml of tetrahydrofuran to form a deep red solution. The solution was added dropwise with diethylamine (48 mg, 0.66 mmol) to form a purple solution and stirred for 2 hours. The solid rushed into the solution. The mixture was filtered, the filter cake was washed with tetrahydrofuran (1 ml x 3), and the solid product dried in vacuo to obtain the title compound bis- (diethylamine)

del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-carbonil-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3carboxilico 2 (132 mg, rendimiento: 66,7%) en forma de un solido de color rojo. HPLC: 99,2% EM m/z (IEN): 452,9 [M-1] of the acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -biphenyl-3-carboxylic 2 (132 mg, yield: 66.7%) in the form of a red solid. HPLC: 99.2% MS m / z (ESI): 452.9 [M-1]

5 1H RMN (400 MHz, CD3OD): 8 8,08(m, 1H), 7,94 (d, J = 7,6 Hz, 1H), 7,72 (m, 2H), 7,62 (m, 2H), 7,55 (m, 1H), 7,25 (d, J = 8,4 Hz, 1H), 7,14 (d, J = 8,4 Hz, 1H), 7,07 (m, 1H), 2,89-2,98 (m, 12H), 2,38 (s, 3H), 2,09-2,14 (m, 2H), 1,34 (m, 12H) 5 1H NMR (400 MHz, CD3OD): 8 8.08 (m, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.72 (m, 2H), 7.62 (m , 2H), 7.55 (m, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.07 (m , 1H), 2.89-2.98 (m, 12H), 2.38 (s, 3H), 2.09-2.14 (m, 2H), 1.34 (m, 12H)

Ejemplo 3: bis-(piperazina) del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)10 hidrazino]-bifenil-3-carboxilico Example 3: bis- (piperazine) of the acid (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazole -4-ylidene) 10 hydrazino] -biphenyl-3-carboxylic

Se disolvio acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-carbonil-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3(Z) -2'-Hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydro-pyrazol-4-ylidene) -hydrazino acid was dissolved ] -biphenyl-3

15 carboxilico 1j (150 mg, 0,33 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con piperazina (57 mg, 0,66 mmol) para formar una solucion de color purpura, y se agito a temperatura ambiente durante 2 horas. El solido se precipito en la solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(piperazina) del acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-carbonil-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3-carboxilico 3 Carboxylic 1j (150 mg, 0.33 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with piperazine (57 mg, 0.66 mmol) to form a purple solution, and stirred at room temperature for 2 hours. The solid was precipitated in the solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (piperazine) of the acid (Z) -2 ' -hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -biphenyl-3-carboxylic acid 3

20 (130 mg, rendimiento: 62,8%) en forma de un solido de color rojo intenso. HPLC: 98,5% EM m/z (IEN): 452,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 8,10 (s, 1H). 7,92 (d, J = 7,6 Hz, 1H), 7,68 (m, 3H), 7,61 (m, 1H), 7,43 (m, 1H), 7,24 (d, J = 8,0 Hz, 1H). 7,15 (m, 1H), 7,00 (m, 1H), 2,89-2,95(m, 4H), 2,84 (s, 16H), 2,39 (s, 3H), 2,09-2,12 (m, 2H) 20 (130 mg, yield: 62.8%) in the form of an intense red solid. HPLC: 98.5% MS m / z (ESI): 452.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 8.10 (s, 1H). 7.92 (d, J = 7.6 Hz, 1H), 7.68 (m, 3H), 7.61 (m, 1H), 7.43 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H). 7.15 (m, 1H), 7.00 (m, 1H), 2.89-2.95 (m, 4H), 2.84 (s, 16H), 2.39 (s, 3H), 2 , 09-2.12 (m, 2H)

25 Ejemplo 4: bis-(etanolamina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4ilideno]-hidrazino}-2-hidroxi-fenil)-furan-2-carboxilico Etapa 1 Example 4: bis- (ethanolamine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1 , 5-dihydro-pyrazol-4-ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic Step 1

1-(3,3-dimetil-inden-5-il)hidrazina-1,2-dicarboxilato de di-terc-butilo Di-tert-butyl 1- (3,3-dimethyl-inden-5-yl) hydrazine-1,2-dicarboxylate

Se disolvio 6-bromo-1,1-dimetil-indano (preparado usando un procedimiento ya conocido: solicitud de patente WO 2005/066115) 4a (4,32 g, 19,27 mmol) en 40 ml de tetrahidrofurano y despues se afadio gota a gota butil litio (15,67 ml, 1,6 M, 25,05 mmol) a -78 °C. Despues de que la mezcla de reaccion se hizo reaccionar durante 40 minutos, se afadio entonces una solucion de azodicarboxilato de di-terc-butilo (5,32 g, 23,12 mmol) en 30 ml de tetrahidrofurano. La mezcla de reaccion se hizo reaccionar durante 3 horas mas a -78 °C. La mezcla de reaccion se afadio con 5 ml de metanol, despues se calento hasta la temperatura ambiente y se filtro mediante gel de silice. El filtrado se concentro a presion reducida y el residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo 1-(3,3-dimetil-1H-inden-5-il)hidrazina-1,2-dicarboxilato de di-terc-butilo 5b (2,70 g, rendimiento del 37,2%) en forma de un solido de color amarillo. 6-Bromo-1,1-dimethyl-indane (prepared using a known procedure: patent application WO 2005/066115) 4a (4.32 g, 19.27 mmol) was dissolved in 40 ml of tetrahydrofuran and then added dropwise butyl lithium (15.67 ml, 1.6 M, 25.05 mmol) at -78 ° C. After the reaction mixture was reacted for 40 minutes, then a solution of di-tert-butyl azodicarboxylate (5.32 g, 23.12 mmol) in 30 ml of tetrahydrofuran was added. The reaction mixture was reacted for a further 3 hours at -78 ° C. The reaction mixture was added with 5 ml of methanol, then heated to room temperature and filtered by silica gel. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 1- (3,3-dimethyl-1H-inden-5-yl) hydrazine-1,2- di-tert-butyl dicarboxylate 5b (2.70 g, 37.2% yield) as a yellow solid.

Etapa 2 Stage 2

2-(3,3-Dimetil-indan-5-il)-5-metil-2,4-dihidro-pirazol-3-ona 2- (3,3-Dimethyl-indan-5-yl) -5-methyl-2,4-dihydro-pyrazol-3-one

Se disolvio 1-(3,3-dimetil-1H-inden-5-il)hidrazina-1,2-dicarboxilato de di-terc-butilo 4b (2,70 g, 7,18 mmol) en 100 ml de acido acetico seguido de la adicion de 20 ml de acido trifluoroacetico. Despues de que la mezcla se hiciera reaccionar a temperatura ambiente durante 2 horas, se afadio acetoacetato de etilo (0,98 g, 7,54 mmol). Despues, la mezcla se calento a 100 °C y se hizo reaccionar durante 2 horas. La mezcla se enfrio a temperatura ambiente y se concentro a presion reducida para retirar el acido acetico. La mezcla de reaccion se neutralizo por una solucion saturada de bicarbonato sodico, y despues se extrajo con acetato de etilo. Los extractos organicos combinados se lavaron con salmuera saturada, se secaron sobre sulfato sodico anhidro, se filtraron y se concentraron a presion reducida. El residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo 2-(3,3-dimetil-indan-5-il)-5-metil-2,4-dihidro-pirazol-3-ona 5c (1,0 g, rendimiento del 47,7%) en forma de un solido de color pardo claro. EM m/z (IEN): 243 [M+1] 1- (3,3-Dimethyl-1H-inden-5-yl) hydrazine-1,2-dicarboxylate di-tert-butyl 4b (2.70 g, 7.18 mmol) was dissolved in 100 ml of acetic acid followed by the addition of 20 ml of trifluoroacetic acid. After the mixture was reacted at room temperature for 2 hours, ethyl acetoacetate (0.98 g, 7.54 mmol) was added. Then, the mixture was heated to 100 ° C and reacted for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The reaction mixture was neutralized by a saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain the title compound 2- (3,3-dimethyl-indan-5-yl) -5-methyl-2,4-dihydro-pyrazol-3-one 5c (1.0 g, 47.7% yield) in the form of a light brown solid. MS m / z (ESI): 243 [M + 1]

Etapa 3 Stage 3

2-(2-Metoxi-3-nitro-fenil)-4,4,5,5-tetrametil-[1,3,2]dioxaborolano 2- (2-Methoxy-3-nitro-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

Se disolvieron 1-bromo-2-metoxi-3-nitro-benceno 1c (67 g, 289 mmol), 4,4,4',4',5,5,5',5'-octametil-2,2'-bi-1,3,2dioxaborolano (110 g, 433 mmol), tetraquis(trifenilfosfina)paladio (11,80 g, 14,44 mmol) y acetato potasico (71 g, 724 mmol) en 600 ml de eter dimetilico del acido eteroxalico. La mezcla se calento a reflujo durante 17 horas. La mezcla se concentro a presion reducida y el residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo 2-(2-metoxi-3-nitro-fenil)-4,4,5,5-tetrametil-[1,3,2]dioxaborolano 4d (50,5 g, 61,9%) en forma de un cristal de color amarillo. 1-Bromo-2-methoxy-3-nitro-benzene 1c (67 g, 289 mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2' were dissolved -bi-1,3,2-dioxaborolane (110 g, 433 mmol), tetrakis (triphenylphosphine) palladium (11.80 g, 14.44 mmol) and potassium acetate (71 g, 724 mmol) in 600 ml of dimethyl ether of the acid Eteroxalic The mixture was heated at reflux for 17 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 2- (2-methoxy-3-nitro-phenyl) -4,4,5,5-tetramethyl - [1,3,2] dioxaborolane 4d (50.5 g, 61.9%) in the form of a yellow crystal.

Etapa 4 Stage 4

Acido 5-(2-metoxi-3-nitro-fenil)furan-2-carboxilico 5- (2-Methoxy-3-nitro-phenyl) furan-2-carboxylic acid

Se disolvieron 2-(2-metoxi-3-nitro-fenil)-4,4,5,5-tetrametil-[1,3,2]dioxaborolano 4d (10 g, 35,85 mmol), acido 5bromofuran-2-carboxilico (5,47 g, 28,66 mmol), tetraquis(trifenilfosfina)paladio (2,07 g, 1,79 mmol) y carbonato sodico (7,60 g, 71,66 mmol) en la mezcla de disolvente de 200 ml de 1,4-dioxano y 30 ml de agua. La mezcla de reaccion se calento a reflujo durante 2,5 horas. La mezcla se filtro y el filtrado se concentro a presion reducida. El residuo se diluyo con 150 ml de agua y se ajusto a pH 3 con acido clorhidrico 1 M. Despues, la mezcla se filtro y la torta de filtro se lavo con 50 ml de la mezcla de disolvente de n-hexano/acetato de etilo (V/V = 1:1). El residuo se seco para obtener el compuesto del titulo acido 5-(2-metoxi-3-nitrofenil) furan-2-carboxilico 4e (4,23 g, rendimiento del 56,1%) en forma de un solido de color gris. EM m/z (IEN): 262 [M-1] 2- (2-Methoxy-3-nitro-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane 4d (10 g, 35.85 mmol), 5bromofuran-2- acid were dissolved carboxylic (5.47 g, 28.66 mmol), tetrakis (triphenylphosphine) palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) in the solvent mixture of 200 ml of 1,4-dioxane and 30 ml of water. The reaction mixture was heated at reflux for 2.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 ml of water and adjusted to pH 3 with 1 M hydrochloric acid. The mixture was then filtered and the filter cake washed with 50 ml of the n-hexane / ethyl acetate solvent mixture. (V / V = 1: 1). The residue was dried to obtain the title compound 5- (2-methoxy-3-nitrophenyl) furan-2-carboxylic acid 4e (4.23 g, 56.1% yield) as a gray solid. MS m / z (ESI): 262 [M-1]

Etapa 5 Stage 5

Acido 5-(3-amino-2-metoxi-fenil)-furan-2-carboxilico 5- (3-Amino-2-methoxy-phenyl) -furan-2-carboxylic acid

Se disolvio acido 5-(2-metoxi-3-nitro-fenil)furan-2-carboxilico 4e (4,23 g, 16,09 mmol) en 125 ml de acetato de etilo seguido de la adicion de 423 mg de paladio sobre carbono (10%) y formiato amonico (4,054 g, 64,35 mmol). La mezcla de reaccion se calento a reflujo durante 3,5 horas. La mezcla se concentro a presion reducida y el residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo acido 5(3-amino-2-metoxi-fenil)-furan-2-carboxilico 4f (2,79 g, rendimiento del 74,4%) en forma de un solido de color verde claro. EM m/z (IEN): 232 [M-1] 5- (2-Methoxy-3-nitro-phenyl) furan-2-carboxylic acid 4e (4.23 g, 16.09 mmol) was dissolved in 125 ml of ethyl acetate followed by the addition of 423 mg of palladium on carbon (10%) and ammonium formate (4,054 g, 64.35 mmol). The reaction mixture was heated at reflux for 3.5 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound acid 5 (3-amino-2-methoxy-phenyl) -furan-2-carboxylic acid 4f (2, 79 g, 74.4% yield) in the form of a light green solid. MS m / z (ESI): 232 [M-1]

Etapa 6 Stage 6

Bromhidrato del acido 5-(3-amino-2-hidroxi-fenil)-furan-2-carboxilico 5- (3-Amino-2-hydroxy-phenyl) -furan-2-carboxylic acid hydrobromide

Se disolvio acido 5-(3-amino-2-metoxi-fenil)-furan-2-carboxilico 4f (2,79 g, 11,97 mmol) en 25 ml de diclorometano seguido de la adicion gota a gota de tribromuro de boro (23,9 ml, 2,0 M). La mezcla de reaccion se hizo reaccionar a temperatura ambiente durante 1 hora. La mezcla se concentro a presion reducida despues de afadir 5 ml de metanol. El residuo se diluyo con 100 ml de acetato de etilo y se agito durante 1 hora. Despues, la mezcla se filtro y la torta de filtro se seco para obtener el compuesto del titulo bromhidrato del acido 5-(3-amino-2-hidroxi-fenil)-furan2-carboxilico 49 (1,24 g, rendimiento del 47,2%) en forma de un solido de color amarillo. EM m/z (IEN): 218 [M-1] 5- (3-Amino-2-methoxy-phenyl) -furan-2-carboxylic acid 4f (2.79 g, 11.97 mmol) was dissolved in 25 ml of dichloromethane followed by the dropwise addition of boron tribromide (23.9 ml, 2.0 M). The reaction mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure after adding 5 ml of methanol. The residue was diluted with 100 ml of ethyl acetate and stirred for 1 hour. Then, the mixture was filtered and the filter cake dried to obtain the title compound 5- (3-amino-2-hydroxy-phenyl) -furan2-carboxylic acid 49 hydrochloride (1.24 g, 47 yield, 2%) in the form of a yellow solid. MS m / z (ESI): 218 [M-1]

Etapa 7 Stage 7

Acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1, 5-dihidro-pirazol-4-ilideno]-hidrazino}-2-hidroxi-fenil)furan-2-carboxilico (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1, 5-dihydro-pyrazol-4-ylidene acid ] -hydrazino} -2-hydroxy-phenyl) furan-2-carboxylic

Se disolvio bromhidrato del acido (Z)-5-(3-amino-2-hidroxi-fenil)-furan-2-carboxilico 49 (333 mg, 1,1 mmol) en acido clorhidrico (3,7 ml, 1 M) tras la refrigeracion en un bafo de hielo-agua seguido de la adicion gota a gota de 1,5 ml de una solucion de nitrito sodico (85 mg, 1,22 mmol). Despues de que la mezcla se hiciera reaccionar durante 20 minutos, se afadieron sucesivamente 2-(3,3-dimetil-indan-5-il)-5-metil-2,4-dihidro-pirazol-3-ona 5c (242 mg, 1,0 mmol), bicarbonato sodico (1,4 g, 16,67 mmol) y 3 ml de etanol. La mezcla de reaccion se hizo reaccionar durante una noche a temperatura ambiente. La mezcla se filtro y a la torta de filtro se le afadieron 20 ml de agua. La mezcla se ajusto a pH 3 4 con acido clorhidrico concentrado. La mezcla se filtro y la torta de filtro se seco y se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo acido (Z)-5-(3-{N'-[1-(3,3-dimetilindan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2-hidroxi-fenil)-furan-2-carboxilico 4h (190 mg, rendimiento del 40,3%) en forma de un solido de color rojo. EM m/z (IEN): 470,9 [M-1] 1H RMN (400 MHz, DMSO-d6): 8 13,74(s a, 1H), 13,15(s a, 1H), 9,99(s a, 1H), 7,71 (m, 3H), 7,55 (d, J = 6,8 Hz, 1H), 7,37 (d, J = 3,6 Hz, 1H), 7,20 (m, 2H), 7,15 (m, 1H), 2,86 (t, J = 7,2 Hz, 2H), 2,33 (s, 3H), 1,92 (t, J = 7,2 Hz, 2H), 1,26 (s, 6H) (Z) -5- (3-Amino-2-hydroxy-phenyl) -furan-2-carboxylic acid hydrobromide 49 (333 mg, 1.1 mmol) was dissolved in hydrochloric acid (3.7 ml, 1 M) after cooling in an ice-water bath followed by the dropwise addition of 1.5 ml of a solution of sodium nitrite (85 mg, 1.22 mmol). After the mixture was reacted for 20 minutes, 2- (3,3-dimethyl-indan-5-yl) -5-methyl-2,4-dihydro-pyrazol-3-one 5c (242 mg) were added successively , 1.0 mmol), sodium bicarbonate (1.4 g, 16.67 mmol) and 3 ml of ethanol. The reaction mixture was reacted overnight at room temperature. The mixture was filtered and 20 ml of water was added to the filter cake. The mixture was adjusted to pH 3 4 with concentrated hydrochloric acid. The mixture was filtered and the filter cake dried and purified by silica gel column chromatography to obtain the title compound acid (Z) -5- (3- {N '- [1- (3,3- dimethylindan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic acid 4h (190 mg, yield of 40.3%) in the form of a red solid. MS m / z (ESI): 470.9 [M-1] 1H NMR (400 MHz, DMSO-d6): 8 13.74 (sa, 1H), 13.15 (sa, 1H), 9.99 ( sa, 1H), 7.71 (m, 3H), 7.55 (d, J = 6.8 Hz, 1H), 7.37 (d, J = 3.6 Hz, 1H), 7.20 ( m, 2H), 7.15 (m, 1H), 2.86 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.92 (t, J = 7.2 Hz, 2H), 1.26 (s, 6H)

Etapa 8 Stage 8

bis-(etanolamina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]hidrazino}-2-hidroxi-fenil)-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro -pyrazol-4-ylidene] hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic

Se disolvio acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2hidroxi-fenil)-furan-2-carboxilico 4h (2,3 g, 4,87 mmol) en 20 ml de tetrahidrofurano. La solucion se afadio con etanolamina (594 mg, 9,75 mmol) y se agito durante 1 hora a temperatura ambiente. La mezcla se filtro, la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(etanolamina) del acido (Z)-S-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2-hidroxi-fenil)furan-2-carboxilico 4 (2,5 g, rendimiento: 86,4%) en forma de un solido de color negro. EM m/z (IEN): 470,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,57 (m, 4H), 7,19 (m, 1H), 7,03 (d, J = 3,6 Hz, 1H), 6,95 (d, J = 3,6 Hz, 1H), 6,71 (t, J = 8,0 Hz, 1H), 3,73 (t, J = 5,2 Hz, 4H), 2,98 (m, 4H), 2,88 (t, J = 7,2 Hz, 2H), 2,36 (s, 3H), 1,96 (t, J = 7,2 Hz, 2H), 1,29 (s, 6H) Acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4) was dissolved -ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic acid 4h (2.3 g, 4.87 mmol) in 20 ml of tetrahydrofuran. The solution was added with Ethanolamine (594 mg, 9.75 mmol) and stirred for 1 hour at room temperature. The mixture is filtered, the cake filter was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (ethanolamine) of the acid (Z) -S- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4- ilidene] -hydrazino} -2-hydroxy-phenyl) furan-2-carboxylic 4 (2.5 g, yield: 86.4%) as a black solid. MS m / z (ESI): 470.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.57 (m, 4H), 7.19 (m, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 3.6 Hz, 1H), 6.71 (t, J = 8.0 Hz, 1H), 3.73 (t, J = 5.2 Hz, 4H), 2.98 (m, 4H), 2.88 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.96 (t, J = 7.2 Hz, 2H), 1.29 (s, 6H)

Ejemplo 5: bis-(dietilamina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4ilideno]-hidrazino}-2-hidroxi-fenil)-furan-2-carboxilico Example 5: bis- (diethylamine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1, 5-dihydro-pyrazol-4-ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2hidroxi-fenil)-furan-2-carboxilico 4h (150 mg, 0,32 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con dietilamina (46 mg, 0,63 mmol) para formar una solucion de color purpura, y se agito a temperatura ambiente durante una noche. La solucion se concentro a presion reducida, el residuo resultante se purifico por cromatografia en columna sobre gel de silice (hexano:acetato de etilo = 10:1), y el producto solido se seco al vacio para obtener el compuesto del titulo bis(dietilamina) del acido (Z)-5-(3-{N'-[1-(3,3dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2-hidroxi-fenil)-furan-2-carboxilico 5 (170 mg, rendimiento: 86,7%) en forma de un solido de color rojo intenso. HPLC: 94,6% EM m/z (IEN): 471,9 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,60 (m, 4H), 7,19 (m, 1H), 7,04 (m, 1H), 6,87 (m, 2H), 2,98 (c, J = 7,2 Hz, 8H), 2,89 (t, J = 7,2 Hz, 2H), 2,36 (s, 3H), 1,96 (t, J = 7,2 Hz, 2H), 1,27 (t, J = 7,2 Hz, 12H), 1,25 (s, 6H) Acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4) was dissolved -ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic acid 4h (150 mg, 0.32 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with diethylamine (46 mg, 0.63 mmol) to form a purple solution, and stirred at room temperature overnight. The solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the solid product dried in vacuo to obtain the title compound bis (diethylamine ) of (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) ] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic 5 (170 mg, yield: 86.7%) as an intense red solid. HPLC: 94.6% MS m / z (ESI): 471.9 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.60 (m, 4H), 7.19 (m, 1H), 7.04 (m, 1H), 6.87 (m, 2H), 2.98 (c, J = 7.2 Hz, 8H), 2.89 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.96 (t, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 12H), 1.25 (s, 6H)

Ejemplo 6: bis-(piperazina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4ilideno]-hidrazino}-2-hidroxi-fenil)-furan-2-carboxilico Example 6: bis- (piperazine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1, 5-dihydro-pyrazol-4-ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2hidroxi-fenil)-furan-2-carboxilico 4h (150 mg, 0,32 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con piperazina (55 mg, 0,64 mmol) para formar una solucion de color purpura, y se agito a temperatura ambiente durante una noche. La mezcla se filtro, la torta de filtro se lavo con tetrahidrofurano (1 ml x 3), y el producto solido se seco al vacio para obtener el compuesto del titulo bis-(piperazina) del acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-2-hidroxi-fenil)furan-2-carboxilico 6 (158 mg, rendimiento: 77,1%) en forma de un solido de color rojo. HPLC: 99,28% EM m/z (IEN): 471,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,64-7,66 (m, 3H), 7,55 (d, J = 8,0 Hz, 1H), 7,21(d, J = 8,0 Hz,1H), 7,04 (m, 1H), 6,876,88 (m, 2H), 3,01 (s, 16H), 2,90 (t, J = 7,2 Hz,2H), 2,38 (s, 3H), 1,97 (t, J = 7,2 Hz,2H), 1,29 (s, 6H) Ejemplo 7: bis-(etanolamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4) was dissolved -ylidene] -hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic acid 4h (150 mg, 0.32 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with piperazine (55 mg, 0.64 mmol) to form a purple solution, and stirred at room temperature overnight. The mixture was filtered, the filter cake was washed with tetrahydrofuran (1 ml x 3), and the solid product was dried in vacuo to obtain the title compound bis- (piperazine) of the acid (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -2-hydroxy-phenyl ) furan-2-carboxylic 6 (158 mg, yield: 77.1%) in the form of a red solid. HPLC: 99.28% MS m / z (ESI): 471.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.64-7.66 (m, 3H), 7.55 (d , J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.04 (m, 1H), 6.876.88 (m, 2H), 3.01 (s , 16H), 2.90 (t, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.97 (t, J = 7.2 Hz, 2H), 1.29 (s , 6H) Example 7: bis- (ethanolamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8- tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Etapa 1 Stage 1

(5,6,7,8-Tetrahidro-naftalen-2-il)-hidrazina (5,6,7,8-Tetrahydro-naphthalen-2-yl) -hydrazine

10 Se disolvio 5,6,7,8-tetrahidro-naftalen-2-ilamina 7a (3,68 g, 25,0 mmol) en 20 ml de acido clorhidrico concentrado y la mezcla se agito durante 10 minutos tras la refrigeracion en un bafo de hielo-agua. Se afadieron gota a gota 10 ml de una solucion de nitrito sodico (1,72 g, 25,0 mmol) y la mezcla se agito durante 15 minutos mas y se uso en la siguiente reaccion. 10 5,6,7,8-tetrahydro-naphthalen-2-ylamine 7a (3.68 g, 25.0 mmol) was dissolved in 20 ml of concentrated hydrochloric acid and the mixture was stirred for 10 minutes after cooling in a bafo of ice-water. 10 ml of a solution of sodium nitrite (1.72 g, 25.0 mmol) was added dropwise and the mixture was stirred for a further 15 minutes and used in the next reaction.

15 Despues de la refrigeracion en un bafo de hielo-sal, se disolvio cloruro estannoso dihidrato (22,6 g, 100 mmol) en 10 ml de acido clorhidrico concentrado seguido de la adicion de la mezcla auxiliar que se ha mencionado anteriormente. La mezcla de reaccion se calento hasta la temperatura ambiente y se hizo reaccionar durante 1,5 horas. Despues, la mezcla se ajusto a pH 9 con una solucion al 40% de hidroxido sodico. La mezcla se extrajo con 400 ml de acetato de After cooling in an ice-salt bath, stannous chloride dihydrate (22.6 g, 100 mmol) was dissolved in 10 ml of concentrated hydrochloric acid followed by the addition of the auxiliary mixture mentioned above. The reaction mixture was heated to room temperature and reacted for 1.5 hours. Then, the mixture was adjusted to pH 9 with a 40% solution of sodium hydroxide. The mixture was extracted with 400 ml of acetate

20 etilo, despues los extractos organicos combinados se concentraron a presion reducida y se secaron para obtener el compuesto del titulo (5,6,7,8-tetrahidro-naftalen-2-il)-hidrazina 7b (2,19 g, rendimiento del 53,7%) en forma de un aceite de color amarillo. EM m/z (IEN): 163 [M+1] Ethyl, then the combined organic extracts were concentrated under reduced pressure and dried to obtain the title compound (5,6,7,8-tetrahydro-naphthalen-2-yl) -hydrazine 7b (2.19 g, yield of 53.7%) in the form of a yellow oil. MS m / z (ESI): 163 [M + 1]

25 Etapa 2 25 Stage 2

5-Metil-2-(5,6,7,8-tetrahidro-naftalen-2-il)-2,4-dihidro-pirazol-3-ona 5-Methyl-2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -2,4-dihydro-pyrazol-3-one

Se disolvio (5,6,7,8-tetrahidro-naftalen-2-il)-hidrazina 7b (2,0 g, 12,3 mmol) en 50 ml de acido acetico seguido de la (5,6,7,8-tetrahydro-naphthalen-2-yl) -hydrazine 7b (2.0 g, 12.3 mmol) was dissolved in 50 ml of acetic acid followed by

30 adicion de acetoacetato de etilo (1,57 ml, 12,3 mmol). La mezcla de reaccion se calento a 100 °C durante una noche. La mezcla se concentro a presion reducida y el residuo resultante se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo 5-metil-2-(5,6,7,8-tetrahidro-naftalen-2-il)-2,4-dihidro-pirazol-3-ona 7c (1,58 g, rendimiento del 56,2%) en forma de un aceite incoloro. EM m/z (IEN): 457 [2M+1]30 addition of ethyl acetoacetate (1.57 ml, 12.3 mmol). The reaction mixture was heated at 100 ° C overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-methyl-2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -2,4-dihydro-pyrazol-3-one 7c (1.58 g, 56.2% yield) as a colorless oil. MS m / z (ESI): 457 [2M + 1]

35 1H RMN (CDCl3): 8 7,54-7,58 (m, 2H), 7,09 (d, J = 8 Hz, 1H), 3,43 (s, 2H), 2,77-2,81 (m, 4H), 2,21 (s, 3H), 1,80-1,83 (m, 4H). 1 H NMR (CDCl 3): 8 7.54-7.58 (m, 2H), 7.09 (d, J = 8 Hz, 1H), 3.43 (s, 2H), 2.77-2, 81 (m, 4H), 2.21 (s, 3H), 1.80-1.83 (m, 4H).

Etapa 3 Stage 3

40 Acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}fenil)-furan-2-carboxilico 40 (Z) -5- (2-Hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1, 5-dihydro-pyrazol-4-ylidene] -hydrazino} phenyl) -furan-2-carboxylic acid

Se disolvio bromhidrato del acido 5-(3-amino-2-hidroxi-fenil)-furan-2-carboxilico 49 (292 mg, 0,98 mmol) en 3,3 ml de acido clorhidrico 1 M tras la refrigeracion en un bafo de hielo-agua seguido de la adicion gota a gota de 1,3 ml de una solucion de nitrito sodico (74 mg, 1,07 mmol). Despues de que la mezcla se agitara durante 20 minutos, se afadio 5-metil-2-(5,6,7,8-tetrahidro-naftalen-2-il)-2,4-dihidro-pirazol-3-ona 7c (200 mg, 0,88 mmol). La mezcla se ajusto a pH 8-9 mediante una adicion en lotes de una solucion de bicarbonato sodico (1,226 g, 14,6 mmol). Las burbujas generadas se inactivaron con 2 ml de etanol. La mezcla de reaccion se calento hasta la temperatura ambiente y se hizo reaccionar durante una noche. La mezcla se filtro y la torta de filtro se disolvio en 20 ml de agua. Despues de mezclarla bien, la mezcla se ajusto a pH 3-4 con acido clorhidrico concentrado, se filtro y se seco. El producto en bruto se purifico por HPLC para obtener el compuesto del titulo acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 7d (160 mg, rendimiento del 39,8%) en forma de un solido de color rojo. EM m/z (IEN): 457 [M-1] 1H RMN (400 MHz, DMSO-d6): 8 7,71(d, J = 8,4 Hz, 1H), 7,63 (m, 2H), 7,56 (d, J = 7,6 Hz, 1H), 7,37 (d, J = 3,2 Hz, 1H), 7,22 (t, J = 8,0 Hz, 1H), 7,13 (m, 2H), 2,75 (m, 4H), 2,33 (s, 3H),1,76 (m, 4H) 5- (3-Amino-2-hydroxy-phenyl) -furan-2-carboxylic acid 49 hydrochloride (292 mg, 0.98 mmol) was dissolved in 3.3 ml of 1 M hydrochloric acid after cooling in an ice-water bath followed by the dropwise addition of 1.3 ml of a solution of sodium nitrite (74 mg, 1.07 mmol). After the mixture was stirred for 20 minutes, it was Afadium 5-methyl-2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -2,4-dihydro-pyrazol-3-one 7c (200 mg, 0.88 mmol). The mixture is adjusted to pH 8-9 by a batch addition of a sodium bicarbonate solution (1,226 g, 14.6 mmol). The Bubbles generated were quenched with 2 ml of ethanol. The reaction mixture was heated to temperature. atmosphere and reacted overnight. The mixture was filtered and the filter cake was dissolved in 20 ml of water. After mixing it well, the mixture was adjusted to pH 3-4 with concentrated hydrochloric acid, filtered and dried. He The crude product was purified by HPLC to obtain the title compound acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5oxo-1- (5,6,7,8-tetrahydro -naftalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic 7d (160 mg, 39.8% yield) in the form of a red solid. MS m / z (ESI): 457 [M-1] 1H NMR (400 MHz, DMSO-d6): 8 7.71 (d, J = 8.4 Hz, 1H), 7.63 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.13 (m, 2H), 2.75 (m, 4H), 2.33 (s, 3H), 1.76 ( m, 4H)

Etapa 4 Stage 4

bis-(etanolamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-di-hidro-pirazol4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2- il) -1,5-di-hydro-pyrazol4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 7d (3,3 g, 7,2 mmol) en 15 ml de tetrahidrofurano. La solucion de reaccion se afadio gota a gota lentamente con etanolamina (0,88 g, 13 mmol), y se agito durante 1,5 horas a 15-20 °C. Una gran cantidad de solido se precipito en la solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (10 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(etanolamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 7 (3 g, rendimiento: 74%) en forma de un solido de color rojo intenso. HPLC: 99,3% EM m/z (IEN): 456,8 [M-1] 1H RMN (400 MHz, CH3OD): 87,51 (d, J = 8,0 Hz, 1H), 7,44-7,46 (m, 3H), 6,93-6,98 (m, 2H), 6,88 (d, J = 3,6 Hz, 1H), 6,67 (t, J = 8,0 Hz, 1H), 3,61 (t, J = 5,2 Hz, 4H), 2,86 (t, J = 5,2 Hz, 4H), 2,65-2,70 (m, 4H), 2,24 (s, 3H), 1,70-1,72 (s, 3H) Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was dissolved , 5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 7d (3.3 g, 7.2 mmol) in 15 ml of tetrahydrofuran. The reaction solution is Add dropwise slowly with ethanolamine (0.88 g, 13 mmol), and stir for 1.5 hours at 15-20 ° C. A a large amount of solid precipitated into the solution, was filtered, then the filter cake was washed with tetrahydrofuran (10 ml x 3) and dried in vacuo to obtain the title compound bis- (ethanolamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3methyl-5-oxo-1- (5 , 6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid 7 (3 g, yield: 74%) in the form of a solid of deep red color. HPLC: 99.3% MS m / z (ESI): 456.8 [M-1] 1H NMR (400 MHz, CH3OD): 87.51 (d, J = 8.0 Hz, 1H), 7.44-7.46 (m, 3H), 6.93-6.98 (m, 2H) , 6.88 (d, J = 3.6 Hz, 1H), 6.67 (t, J = 8.0 Hz, 1H), 3.61 (t, J = 5.2 Hz, 4H), 2.86 (t, J = 5.2 Hz, 4H), 2, 65-2.70 (m, 4H), 2.24 (s, 3H), 1.70-1.72 (s, 3H)

Ejemplo 8: bis-(colina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidropirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 8: bis- (choline) of (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen) acid -2-yl) -1,5-dihydropyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazin}l-fenil)-furan-2-carboxilico 7d (100 mg, 0,22 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con una solucion al 45% de hidroxido de colina en metanol (45 mg, 0,44 mmol) para formar una solucion de color purpura, y se agito durante 1 hora a temperatura ambiente. El solido se precipito en una solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(colina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 8 (140 mg, rendimiento: 96,6%) en forma de un solido de color rojo intenso. HPLC: 98,82% EM m/z (IEN): 457,8 [M-1] 1H RMN (400 MHz, CD3OD): 87,74 (d, J = 8,0 Hz, 1H), 7,60 (m, 3H), 7,08 (m, 3H), 6,91 (t, J = 8,0 Hz, 1H), 3,96 (m, 4H), 3,45 (t, J = 4,8 Hz, 4H), 3,18 (s, 18H), 2,80 (m, 4H), 2,38 (s, 3H),1,84 (m, 4H) Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was dissolved , 5-dihydro-pyrazol-4-ylidene] hydrazin} l-phenyl) -furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) in 5 ml of tetrahydrofuran to form a suspension Intense red. The reaction mixture was added with a 45% solution of choline hydroxide in methanol (45 mg, 0.44 mmol) to form a purple solution, and stirred for 1 hour at room temperature. He solid was precipitated in a solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (choline) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7, 8 tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid 8 (140 mg, yield: 96.6%) in the form of a solid of deep red color. HPLC: 98.82% MS m / z (ESI): 457.8 [M-1] 1H NMR (400 MHz, CD3OD): 87.74 (d, J = 8.0 Hz, 1H), 7.60 (m, 3H), 7.08 (m, 3H), 6.91 (t, J = 8.0 Hz, 1H), 3.96 (m, 4H), 3.45 (t, J = 4.8 Hz, 4H), 3.18 (s, 18H), 2.80 (m, 4H), 2.38 (s, 3H), 1.84 ( m, 4H)

Ejemplo 9: bis-(dietilamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 9: bis- (diethylamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen) -2-yl) -1,5dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 7d (100 mg, 0,22 mmol) en 5 ml de tetrahidrofurano para formar una suspension 5 de color rojo intenso. La mezcla de reaccion se afadio gota a gota con dietilamina (32 mg, 0,44 mmol) para formar una solucion de color purpura, y se agito a temperatura ambiente durante una noche. El solido se precipito en una solucion, se filtro, y la torta de filtro se lavo con tetrahidrofurano (1 ml x 3), el solido se seco al vacio para obtener el compuesto del titulo bis-(dietilamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 9 (77 mg, rendimiento: 58,3%) en forma de un solido Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was dissolved , 5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added dropwise with diethylamine (32 mg, 0.44 mmol) to form a purple solution, and stirred at room temperature overnight. The solid was precipitated in a solution, filtered, and the filter cake was washed with tetrahydrofuran (1 ml x 3), the solid was dried in vacuo to obtain the title compound bis- (diethylamine) of the acid (Z) - 5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) 1,5-dihydro-pyrazol-4 -ilidene] -hydrazino} -phenyl) -furan-2-carboxylic 9 (77 mg, yield: 58.3%) as a solid

10 de color rojo intenso. HPLC: 99,1% EM m/z (IEN): 457,9 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,59(m, 4H), 7,08 (d, J = 8,0 Hz, 1H), 7,04 (d, J = 3,6 Hz, 1H), 6,94 (d, J = 3,6 Hz, 1H), 6,82 (t, J = 8,0 Hz, 1H), 2,99 (c, J = 7,2 Hz, 8H), 2,79 (m, 4H), 2,36 (s, 3H), 1,82 (t, J = 3,2 Hz, 4H),1,27 (t, J = 10 deep red. HPLC: 99.1% MS m / z (ESI): 457.9 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.59 (m, 4H), 7.08 (d, J = 8 , 0 Hz, 1H), 7.04 (d, J = 3.6 Hz, 1H), 6.94 (d, J = 3.6 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 2.99 (c, J = 7.2 Hz, 8H), 2.79 (m, 4H), 2.36 (s, 3H), 1.82 (t, J = 3.2 Hz, 4H), 1.27 (t, J =

15 7,2 Hz, 12H) 15 7.2 Hz, 12H)

Ejemplo 10: bis-(meglumina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 10: bis- (meglumine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen) -2-yl) -1,5dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se suspendio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico 7d (100 mg, 0,22 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con meglumina (85 mg, 0,44 mmol), y se agito a Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was suspended -1 , 5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with meglumine (85 mg, 0.44 mmol), and stirred at

25 temperatura ambiente durante una noche. La solucion resultante se afadio con 4 ml de metanol y se concentro a presion reducida para obtener el compuesto del titulo bis-(meglumina) del acido (Z)-5-(2-hidroxi-3-(N'-[3-metil-5-oxo1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 10 (168 mg, rendimiento: 90,8%) en forma de un solido de color rojo intenso. HPLC: 97,7% 25 room temperature overnight. The resulting solution was added with 4 ml of methanol and concentrated under reduced pressure to obtain the title compound bis- (meglumine) of the acid (Z) -5- (2-hydroxy-3- (N '- [3-methyl -5-oxo1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic 10 (168 mg, yield: 90.8%) in the form of an intense red solid HPLC: 97.7%

30 EM m/z (IEN): 457,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,56 (m, 4H), 7,06 (m, 2H), 6,98 (d, J = 3,2 Hz, 1H), 6,75 (t, J = 7,6 Hz, 1H), 4,08 (m, 2H), 3,81 (m, 2H), 3,77 (m, 2H), 3,63 (m, 6H), 3,11 (m, 4H), 2,76 (m, 4H), 2,64 (s, 6H), 2,33 (s, 3H), 1,79 (m, 4H) 30 MS m / z (ESI): 457.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.56 (m, 4H), 7.06 (m, 2H), 6.98 (d , J = 3.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 4.08 (m, 2H), 3.81 (m, 2H), 3.77 (m , 2H), 3.63 (m, 6H), 3.11 (m, 4H), 2.76 (m, 4H), 2.64 (s, 6H), 2.33 (s, 3H), 1 , 79 (m, 4H)

Ejemplo 11: bis-(piperazina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,535 dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 11: bis- (piperazine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen) -2-yl) -1,535 dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 7d (100 mg, 0,22 mmol) en 5 ml de tetrahidrofurano para formar una suspension 5 de color rojo intenso. La mezcla de reaccion se afadio con piperazina (37 mg, 0,44 mmol) para formar una solucion de color purpura, y se agito durante 2 horas a temperatura ambiente. El solido se precipito en una solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(piperazina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidropirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 11 (120 mg, rendimiento: 87,6%) en forma de un solido de color Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was dissolved , 5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with piperazine (37 mg, 0.44 mmol) to form a purple solution, and stirred for 2 hours at room temperature. The solid was precipitated in a solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (piperazine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydropyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic 11 (120 mg, yield: 87.6%) as a colored solid

10 rojo intenso. HPLC: 98,8% EM m/z (IEN): 457,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,59(m, 4H), 7,08 (d, J = 8,0 Hz, 1H), 7,04 (d, J = 3,2 Hz, 1H), 6,87 (d, J = 3,2 Hz, 1H), 6,82 (t, J = 8,0 Hz, 1H), 3,00 (s, 16H), 2,78 (m, 4H), 2,36 (s, 3H), 1,81 (m, 4H) 10 deep red. HPLC: 98.8% MS m / z (ESI): 457.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.59 (m, 4H), 7.08 (d, J = 8 , 0 Hz, 1H), 7.04 (d, J = 3.2 Hz, 1H), 6.87 (d, J = 3.2 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 3.00 (s, 16H), 2.78 (m, 4H), 2.36 (s, 3H), 1.81 (m, 4H)

15 Ejemplo 12: bis-(trometamol) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 12: bis- (tromethamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro- naphthalen-2-yl) -1,5dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

20 Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 7d (100 mg, 0,22 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con trometamol (53 mg, 0,44 mmol) para formar una solucion de color pardo, y se agito a temperatura ambiente durante una noche. El solido se precipito en una solucion, se filtro, 20 (Z) -5- (2-Hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) - 1,5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with trometamol (53 mg, 0.44 mmol) to form a brown solution, and stirred at room temperature overnight. The solid precipitated into a solution, was filtered,

25 despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(trometamol) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidropirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 12 (142 mg, rendimiento: 92,8%) en forma de un solido de color oscuro. HPLC: 94,0% Then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (trometamol) of the acid (Z) -5- (2-hydroxy-3- {N ' - [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydropyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2 -carboxylic 12 (142 mg, yield: 92.8%) in the form of a dark solid. HPLC: 94.0%

30 EM m/z (IEN): 457,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,58(m, 4H), 7,05 (m, 2H), 6,96 (d, J = 3,6 Hz, 1H), 6,90 (t, J = 8,0 Hz, 1H), 3,65 (s, 12H), 2,76 (m, 4H), 2,33 (s, 3H), 1,80 (m, 4H) 30 MS m / z (ESI): 457.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.58 (m, 4H), 7.05 (m, 2H), 6.96 (d , J = 3.6 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 3.65 (s, 12H), 2.76 (m, 4H), 2.33 (s , 3H), 1.80 (m, 4H)

Ejemplo 13: bis-(dibenciletilendiamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-235 il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 13: bis- (dibenzylethylenediamine) of (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen) acid -235 il) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 7d (100 mg, 0,22 mmol) en 5 ml de tetrahidrofurano para formar una suspension 5 de color rojo intenso. La mezcla de reaccion se afadio con dibenciletilendiamina (104 mg, 0,44 mmol) para formar una solucion de color pardo, y se agito durante 2 horas a temperatura ambiente. La solucion resultante se afadio con 4 ml de metanol y se concentro a presion reducida para obtener el compuesto del titulo bis(dibenciletilendiamina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidropirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 13 (167 mg, rendimiento: 81,8%) en forma de un solido de color Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was dissolved , 5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with dibenzylethylenediamine (104 mg, 0.44 mmol) to form a brown solution, and stirred for 2 hours at room temperature. The resulting solution was added with 4 ml of methanol and concentrated under reduced pressure to obtain the title compound bis (dibenzylethylenediamine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl- 5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydropyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid 13 (167 mg , yield: 81.8%) in the form of a solid color

10 oscuro. HPLC: 96,8% EM m/z (IEN): 457,8 [M-1] 1H RMN (400 MHz, CD3OD): 87,52-7,54 (m, 3H), 7,39 (d, J = 7,2 Hz, 1H), 7,24-7,28 (m, 20H), 7,01-7,04 (m, 2H), 6,65-6,72 (m, 1H), 3,89 (s, 8H), 3,01 (s, 8H), 2,73 (m, 4H), 2,32 (s, 3H), 1,78 (m, 4H) 10 dark. HPLC: 96.8% MS m / z (ESI): 457.8 [M-1] 1H NMR (400 MHz, CD3OD): 87.52-7.54 (m, 3H), 7.39 (d, J = 7.2 Hz, 1H), 7.24-7.28 (m, 20H), 7.01-7.04 (m, 2H), 6.65-6.72 (m, 1H), 3 , 89 (s, 8H), 3.01 (s, 8H), 2.73 (m, 4H), 2.32 (s, 3H), 1.78 (m, 4H)

15 Ejemplo 14: Sal disodica del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidropirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 14: Disodium salt of acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2 -yl) -1,5-dihydropyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic

20 Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-piraznol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico 7d (110 mg, 0,24 mmol) en 4 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio gota a gota con una solucion 1 M de hidroxido sodico (0,4 ml, 0,44 mmol) y se agito durante 2 horas a temperatura ambiente. La mezcla de reaccion se filtro, 20 (Z) -5- (2-Hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) - 1,5-dihydro-pyraznol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid 7d (110 mg, 0.24 mmol) in 4 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added dropwise with a 1M solution of sodium hydroxide (0.4 ml, 0.44 mmol) and stirred for 2 hours at room temperature. The reaction mixture was filtered,

25 despues el filtrado se afadio con 4 ml de metanol y se concentro a presion reducida. El solido resultante se lavo con hexano para obtener el compuesto del titulo sal disodica del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8tetrahidro-naftalen-2-il)-1,5-di-hidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 14 (115 mg, rendimiento: 81,8%) en forma de un solido de color oscuro. HPLC: 96,8% The filtrate was then added with 4 ml of methanol and concentrated under reduced pressure. The resulting solid was washed with hexane to obtain the title compound disodium salt of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6, 7,8-tetrahydro-naphthalen-2-yl) -1,5-di-hydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic 14 (115 mg, yield: 81.8%) in Shape of a dark solid. HPLC: 96.8%

30 EM m/z (IEN): 457,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,79(dd, J1 = 7,6 Hz, J2 = 1,2 Hz, 1H), 7,52 (m, 3H), 7,18 (d, J = 3,6 Hz, 1H), 7,05 (m, 2H), 6,70 (m, 1H), 2,78 (m, 4H), 2,41 (s, 3H),1,82 (m, 4H) 30 MS m / z (ESI): 457.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.79 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.52 (m, 3H), 7.18 (d, J = 3.6 Hz, 1H), 7.05 (m, 2H), 6.70 (m, 1H), 2.78 (m, 4H ), 2.41 (s, 3H), 1.82 (m, 4H)

Ejemplo 15: bis-(L-arginina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,535 dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 15: bis- (L-arginine) of the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro -naftalen-2-yl) -1,535 dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 7d (100 mg, 0,22 mmol) en 5 ml 1 de tetrahidrofurano para formar una suspension de color rojo intenso La mezcla de reaccion se afadio con L-arginina (76 mg, 0,44 mmol) y 2 ml de agua, se agito durante 2 horas a temperatura ambiente. La solucion de reaccion se concentro a presion reducida, se afadio con 5 ml de acetato de etilo. El solido se precipito en la solucion, se filtro, despues la torta de filtro se seco al vacio para obtener el compuesto del titulo bis-(L-arginina) del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8tetrahidro-naftalen-2-il)-1,5-di-hidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 15 (168 mg, rendimiento: 95,5%) en forma de un solido de color oscuro. HPLC: 97,5% EM m/z (IEN): 457,9 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,59(m, 4H), 7,06 (m, 2H), 6,98 (d, J = 3,6 Hz, 1H), 6,92 (t, J = 8,0 Hz, 1H), 3,57 (t, J = 6,4 Hz, 2H), 3,19 (m, 4H), 2,78 (m, 4H), 2,36 (s, 3H),1,83 (m, 8H), 1,73 (m, 4H) Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was dissolved , 5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 7d (100 mg, 0.22 mmol) in 5 ml 1 of tetrahydrofuran to form a deep red suspension The reaction mixture was added with L-arginine (76 mg, 0.44 mmol) and 2 ml of water, It was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, Add 5 ml of ethyl acetate. The solid precipitated into the solution, was filtered, then the filter cake dried at vacuum to obtain the title compound bis- (L-arginine) from the acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7 , 8-tetrahydro-naphthalen-2-yl) -1,5-di-hydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid (168 mg, yield: 95.5%) in the form of a dark solid. HPLC: 97.5% MS m / z (ESI): 457.9 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.59 (m, 4H), 7.06 (m, 2H), 6.98 (d, J = 3.6 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 3.57 (t, J = 6.4 Hz, 2H), 3.19 (m, 4H), 2.78 (m, 4H), 2.36 (s, 3H), 1.83 (m, 8H), 1.73 (m , 4H)

Ejemplo 16: bis-(etanolamina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4ilideno)-hidrazino]-fenil}-furan-2-carboxilico Example 16: bis- (ethanolamine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene) -hydrazino] -phenyl} -furan-2-carboxylic acid

Etapa 1 Stage 1

Acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-furan-2carboxilico (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino acid] -phenyl} -furan-2-carboxylic

Se disolvio bromhidrato del acido 5-(3-Amino-2-hidroxi-fenil)-furan-2-carboxilico 49 (300 mg, 1,0 mmol) en acido clorhidrico (3,4 ml, 1 M) seguido de la adicion gota a gota de 1,2 ml de una solucion de nitrito sodico (73 mg, 1,05 mmol) tras la refrigeracion en un bafo de hielo-agua. Despues de hacer reaccionar la mezcla durante 10 minutos, se afadieron sucesivamente 2-indan-5-il-5-metil-2,4-dihidro-pirazol-3-ona 1i (193 mg, 0,9 mmol), bicarbonato sodico (1,26 g, 15 mmol) y 4,4 ml de etanol. La mezcla se hizo reaccionar a temperatura ambiente durante 24 horas. La mezcla se filtro y la torta de filtro se lavo con 20 ml de agua y despues se disolvio en 20 ml de agua. Despues de la refrigeracion en un bafo de hielo-agua, la mezcla se ajusto a pH <5 con acido clorhidrico concentrado, se filtro y se seco para obtener el compuesto del titulo acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-45- (3-Amino-2-hydroxy-phenyl) -furan-2-carboxylic acid hydrobromide 49 (300 mg, 1.0 mmol) was dissolved in hydrochloric acid (3.4 ml, 1 M) followed by the addition drop by drop of 1.2 ml of a solution of sodium nitrite (73 mg, 1.05 mmol) after cooling in an ice-water bath. After reacting the mixture for 10 minutes, 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (193 mg, 0.9 mmol), sodium bicarbonate ( 1.26 g, 15 mmol) and 4.4 ml of ethanol. The mixture was reacted at room temperature for 24 hours. The mixture was filtered and the filter cake was washed with 20 ml of water and then dissolved in 20 ml of water. After cooling in an ice-water bath, the mixture was adjusted to pH <5 with concentrated hydrochloric acid, filtered and dried to obtain the title compound acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4

ilideno)-hidrazino]-fenil}-furan-2-carboxilico 16a (287 mg, rendimiento del 71,8%) en forma de un solido de color amarillo. EM m/z (IEN): 443 [M-1] 1H RMN (400 MHz, DMSO-d6): 8 13,73(s a, 1H), 9,97 (s a, 1H), 7,78 (s, 1H), 7,70 (m, 2H), 7,57 (m, 1H), 7,36 (d, J = 3,6 Hz, 1H), 7,29 (d, J = 8,0 Hz, 1H), 7,22 (t, J = 8,0 Hz, 1H), 7,15 (m, 1H), 2,89 (m, 4H), 2,32 (s, 3H),2,03 (m, 2H) ilidene) -hydrazino] -phenyl} -furan-2-carboxylic acid 16a (287 mg, 71.8% yield) as a colored solid yellow. MS m / z (ESI): 443 [M-1] 1H NMR (400 MHz, DMSO-d6): 8 13.73 (sa, 1H), 9.97 (sa, 1H), 7.78 (s, 1H), 7.70 (m, 2H), 7, 57 (m, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.15 (m, 1H), 2 , 89 (m, 4H), 2.32 (s, 3H), 2.03 (m, 2H)

Etapa 2 Stage 2

bis-(etanolamina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4 -ylidene) -hydrazino] phenyl} -furan-2-carboxylic

Se disolvio acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-furan2-carboxilico 16a (1,825 g, 4,11 mmol) en 20 ml de tetrahidrofurano. La mezcla de reaccion se afadio con etanolamina (501 mg, 8,22 mmol), y se agito durante 2 horas a temperatura ambiente. El solido se precipito en una solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(etanolamina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol4-ilideno)-hidrazino]-fenil}-furan-2-carboxilico 16 (1,615 g, rendimiento: 69,4%) en forma de un solido de color rojo intenso. EM m/z (IEN): 443 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,67(s, 1H), 7,53 (m, 3H), 7,21(d, J = 8,0 Hz, 1H), 7,02 (m, 1H), 6,97 (d, J = 3,2 Hz, 1H), 6,70 (m, 1H), 3,70 (m, 4H), 2,92 (m, 4H), 2,88 (m, 4H), 2,35 (s, 3H), 2,08 (m, 2H) Acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) - hydrazino] -phenyl} -furan2-carboxylic acid 16a (1,825 g, 4.11 mmol) in 20 ml of tetrahydrofuran. The reaction mixture was added with Ethanolamine (501 mg, 8.22 mmol), and stirred for 2 hours at room temperature. The solid rushed into a solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the compound of the bis- (ethanolamine) title of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene) -hydrazino] -phenyl} -furan-2-carboxylic 16 (1,615 g, yield: 69.4%) as a red solid intense. MS m / z (ESI): 443 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.67 (s, 1H), 7.53 (m, 3H), 7.21 (d, J = 8.0 Hz, 1H), 7.02 (m, 1H), 6.97 (d, J = 3.2 Hz, 1H), 6.70 (m, 1H), 3.70 (m, 4H), 2.92 (m, 4H), 2.88 (m, 4H), 2.35 (s, 3H), 2, 08 (m, 2H)

Ejemplo 17: bis-(dietilamina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-fenil}-furan-2-carboxilico Example 17: bis- (diethylamine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene) hydrazino] -phenyl} -furan-2-carboxylic

Se suspendio acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}furan-2-carboxilico 16a (150 mg, 0,38 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio gota a gota con dietilamina (49 mg, 0,67 mmol) para formar una solucion de color purpura, y se agito durante 2 horas a temperatura ambiente. El solido se precipito en una solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(dietilamina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-fenil}-furan-2-carboxilico 17 (163 mg, rendimiento: 81,9%) en forma de un solido de color rojo intenso. HPLC: 99,18% EM m/z (IEN): 442,7 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,71 (s, 1H), 7,60 (m, 3H), 7,24 (d, J = 8,0 Hz, 1H), 7,04 (d, J = 8,0 Hz, 1H), 6,95 (d, J = 8,0 Hz, 1H), 6,82 (m, 1H), 3,73 (m, 2H), 2,95 (m, 8H), 2,37 (s, 3H), 2,13 (m, 2H), 1,87 (m, 2H), 1,28 (m, 12H) Acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) - hydrazino] -phenyl} furan-2-carboxylic 16a (150 mg, 0.38 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added dropwise with diethylamine (49 mg, 0.67 mmol) to form a purple solution, and stirred for 2 hours at room temperature. The solid was precipitated in a solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (diethylamine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) hydrazino] -phenyl} -furan-2- carboxylic 17 (163 mg, yield: 81.9%) in the form of an intense red solid. HPLC: 99.18% MS m / z (ESI): 442.7 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.71 (s, 1H), 7.60 (m, 3H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6, 82 (m, 1H), 3.73 (m, 2H), 2.95 (m, 8H), 2.37 (s, 3H), 2.13 (m, 2H), 1.87 (m, 2H ), 1.28 (m, 12H)

Ejemplo 18: bis-(piperazina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-fenil}-furan-2-carboxilico Se disolvio acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-furan2-carboxilico 16a (150 mg, 0,38 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. Example 18: bis- (piperazine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene) hydrazino] -phenyl} -furan-2-carboxylic acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-) 5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -phenyl} -furan2-carboxylic acid 16a (150 mg, 0.38 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension.

5 La mezcla de reaccion se afadio con piperazina (58 mg, 0,68 mmol) para formar una solucion de color purpura, y se agito durante 3 horas a temperatura ambiente. El solido se precipito en una solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(piperazina) del acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-furan-2carboxilico 18 (185 mg, rendimiento: 88,9%) en forma de un solido de color rojo intenso. The reaction mixture was added with piperazine (58 mg, 0.68 mmol) to form a purple solution, and stirred for 3 hours at room temperature. The solid was precipitated in a solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (piperazine) of the acid (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -phenyl} -furan-2-carboxylic acid 18 (185 mg, yield: 88.9%) in the form of an intense red solid.

10 HPLC: 96,52% EM m/z (IEN): 443,2 [M-1] 1H RMN (400 MHz, CD3OD): 87,73 (s, 1H), 7,61-7,64 (m, 2H), 7,55 (d, J = 8,4 Hz, 1H), 7,23 (d, J = 8,4 Hz, 1H), 7,05 (d, J = 8,8 Hz, 1H), 6,78-6,90 (m, 2H), 3,03 (s, 16H), 2,89-2,95 (m, 4H), 2,35 (s, 3H), 2,12 (t, J = 7,2 Hz, 4H) 10 HPLC: 96.52% MS m / z (ESI): 443.2 [M-1] 1H NMR (400 MHz, CD3OD): 87.73 (s, 1H), 7.61-7.64 (m , 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H ), 6.78-6.90 (m, 2H), 3.03 (s, 16H), 2.89-2.95 (m, 4H), 2.35 (s, 3H), 2.12 ( t, J = 7.2 Hz, 4H)

15 Ejemplo 19: bis-(etanolamina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4ilideno)-hidrazino]-fenil}-tiofeno-2-carboxilico Example 19: bis- (ethanolamine) of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro -pyrazol-4-ylidene) -hydrazino] -phenyl} -thiophene-2-carboxylic acid

20 Etapa 1 20 Stage 1

Acido 4-(3-nitro-2-metoxi-fenil)-tiofeno-2-carboxilico 4- (3-Nitro-2-methoxy-phenyl) -thiophene-2-carboxylic acid

25 Se disolvieron 2-(2-metoxi-3-nitro-fenil)-4,4,5,5-tetrametil-1,3,2-dioxaborolano 4d (0,81 g, 2,9 mmol), acido 4-bromotiofeno-2-carboxilico (0,3 g, 1,45 mmol), tetraquis (trifenilfosfina)paladio (80 mg, 0,073 mmol) y carbonato sodico (0,31 g, 2,9 mmol) en una mezcla de disolvente de 20 ml de 1,4-dioxano y 10 ml de agua. La reaccion se calento a 25 2- (2-Methoxy-3-nitro-phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4d (0.81 g, 2.9 mmol), acid 4- bromothiophene-2-carboxylic acid (0.3 g, 1.45 mmol), tetrakis (triphenylphosphine) palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) in a solvent mixture of 20 ml of 1,4-dioxane and 10 ml of water. The reaction was heated to

reflujo durante 0,5 horas. La mezcla se ajusto a pH 3 con acido clorhidrico 1 N y se extrajo con acetato de etilo (20 ml x 3). Los extractos organicos combinados se concentraron a presion reducida y el residuo se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo acido 4-(3-nitro-2-metoxifenil)tiofeno-2-carboxilico 19a (0,54 g) en forma de un aceite de color pardo, que se uso directamente en la siguiente etapa. EM m/z (IEN): 277,6 [M-1] reflux for 0.5 hours. The mixture was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate (20 ml x 3). The combined organic extracts were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to obtain the title compound 4- (3-nitro-2-methoxyphenyl) thiophene-2-carboxylic acid 19a (0.54 g) in the form of a brown oil, which was used directly in the next stage. MS m / z (ESI): 277.6 [M-1]

Etapa 2 Stage 2

Acido 4-(3-amino-2-metoxi-fenil)-tiofeno-2-carboxilico 4- (3-Amino-2-methoxy-phenyl) -thiophene-2-carboxylic acid

Se disolvio acido 4-(3-nitro-2-metoxi-fenil)-tiofeno-2-carboxilico 19a (400 mg, 1,45 mmol) en 30 ml de acetato de etilo seguido de la adicion de 100 mg de paladio sobre carbono (10%) y formiato amonico (360 mg, 5,8 mmol). La mezcla se calento a reflujo durante 3 horas. La mezcla se filtro y se concentro a presion reducida para obtener el compuesto del titulo acido 4-(3-amino-2-metoxi-fenil)-tiofeno-2-carboxilico 19b (410 mg) en forma de un aceite de color pardo, que se uso directamente en la siguiente etapa. EM m/z (IEN): 247,8 [M-1] 4- (3-Nitro-2-methoxy-phenyl) -thiophene-2-carboxylic acid 19a (400 mg, 1.45 mmol) was dissolved in 30 ml of ethyl acetate followed by the addition of 100 mg of palladium on carbon (10%) and ammonium formate (360 mg, 5.8 mmol). Mix It was heated at reflux for 3 hours. The mixture was filtered and concentrated under reduced pressure to obtain the compound. of the title 4- (3-amino-2-methoxy-phenyl) -thiophene-2-carboxylic acid 19b (410 mg) in the form of a brown oil, which was used directly in the next stage. MS m / z (ESI): 247.8 [M-1]

Etapa 3 Stage 3

Bromhidrato del acido 4-(3-amino-2-hidroxi-fenil)-tiofeno-2-carboxilico 4- (3-Amino-2-hydroxy-phenyl) -thiophene-2-carboxylic acid hydrobromide

Se disolvio bromhidrato del acido 4-(3-amino-2-metoxi-fenil)-tiofeno-2-carboxilico 19b (360 mg, 1,45 mmol) en 5 ml de diclorometano seguido de la adicion gota a gota de tribromuro de boro (2,8 ml, 5,6 mmol). La mezcla de reaccion se hizo reaccionar a temperatura ambiente durante 4,5 horas. La mezcla de reaccion se afadio con 5 ml de metanol y se concentro a presion reducida. El residuo se diluyo con 10 ml de acetato de etilo y se agito durante 0,5 horas. La mezcla se filtro y la torta de filtro se seco para obtener el compuesto del titulo bromhidrato del acido 4-(3-amino-2hidroxi-fenil)-tiofeno-2-carboxilico 19c (80 mg, rendimiento del 17,5%) en forma de un solido de color gris. EM m/z (IEN): 236,1 [M+1] 4- (3-Amino-2-methoxy-phenyl) -thiophene-2-carboxylic acid 19b hydrochloride (360 mg, 1.45 mmol) was dissolved in 5 ml dichloromethane followed by the dropwise addition of boron tribromide (2.8 ml, 5.6 mmol). The reaction mixture It was reacted at room temperature for 4.5 hours. The reaction mixture was added with 5 ml of methanol and concentrated under reduced pressure. The residue was diluted with 10 ml of ethyl acetate and stirred for 0.5 hours. The The mixture was filtered and the filter cake dried to obtain the title compound 4- (3-amino-2-hydroxy-phenyl) -thiophene-2-carboxylic acid hydrochloride 19c (80 mg, 17.5% yield) as of a gray solid. MS m / z (ESI): 236.1 [M + 1]

Etapa 4 Stage 4

Acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-tiofeno-2carboxilico (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino acid] -phenyl} -thiophene-2-carboxylic

Se disolvio bromhidrato del acido 4-(3-amino-2-hidroxi-fenil)-tiofeno-2-carboxilico 19c (120 mg, 0,38 mmol) en 2,7 ml de acido clorhidrico 1 M tras la refrigeracion en un bafo de hielo-agua seguido de la adicion gota a gota de 0,45 ml de una solucion de nitrito sodico (29 mg, 0,42 mmol). Despues de que se hiciera reaccionar la mezcla durante 20 minutos, se afadio 2-indan-5-il-5-metil-2,4-dihidro-pirazol-3-ona 1i (73 mg, 0,34 mmol). La mezcla se ajusto a pH 8 con una solucion saturada de bicarbonato sodico seguido de la adicion de 2 ml de etanol. La mezcla de reaccion se hizo reaccionar durante una noche a temperatura ambiente. La mezcla se filtro y la torta de filtro se afadio a 20 ml de agua. La mezcla se ajusto a pH 3-4 con acido clorhidrico concentrado y se filtro. Despues, a la torta de filtro se le afadieron 5 ml de acetato de etilo y la mezcla se agito durante 1 hora. La mezcla se filtro y la torta de filtro se seco para obtener el compuesto del titulo acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4ilideno)-hidrazino]-fenil}-tiofeno-2-carboxilico 19d (45 mg, rendimiento del 28,7%) en forma de un solido de color amarillo. EM m/z (IEN): 458,8 [M-1] 1H RMN (400 MHz, DMSO-d6): 8 13,79 (s a, 1H), 9,68 (s a, 1H), 8,13 (d, J = 1,2 Hz, 1H), 8,05 (d, J = 1,6 Hz, 1H), 7,78 (s, 1H), 7,67 (m, 2H), 7,32 (m, 2H), 7,13 (t, J = 8,0 Hz, 1H), 2,87 (m, 4H), 2,32 (s, 3H), 2,05 (m, 2H) 4- (3-Amino-2-hydroxy-phenyl) -thiophene-2-carboxylic acid 19c hydrochloride (120 mg, 0.38 mmol) was dissolved in 2.7 ml of 1 M hydrochloric acid after cooling in an ice-water bath followed by the dropwise addition of 0.45 ml of a solution of sodium nitrite (29 mg, 0.42 mmol). After the mixture was reacted for 20 minutes, 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (73 mg, 0.34 mmol) was added. The mixture was adjusted to pH 8 with a saturated sodium bicarbonate solution followed by the addition of 2 ml of ethanol. The reaction mixture is It reacted overnight at room temperature. The mixture was filtered and the filter cake was added to 20 ml. of water. The mixture was adjusted to pH 3-4 with concentrated hydrochloric acid and filtered. Then, the filter cake is 5 ml of ethyl acetate was added and the mixture was stirred for 1 hour. The mixture was filtered and the filter cake dried to obtain the title compound acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) ) -hydrazino] -phenyl} -thiophene-2-carboxylic acid 19d (45 mg, 28.7% yield) as a colored solid yellow. MS m / z (ESI): 458.8 [M-1] 1 H NMR (400 MHz, DMSO-d6): 8 13.79 (sa, 1 H), 9.68 (sa, 1 H), 8.13 (d, J = 1.2 Hz, 1 H), 8.05 ( d, J = 1.6 Hz, 1H), 7.78 (s, 1H), 7.67 (m, 2H), 7.32 (m, 2H), 7.13 (t, J = 8.0 Hz, 1H), 2.87 (m, 4H ), 2.32 (s, 3H), 2.05 (m, 2H)

Etapa 5 Stage 5

bis-(etanolamina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]fenil}-tiofeno-2-carboxilico bis- (ethanolamine) of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4 -ylidene) -hydrazino] phenyl} -thiophene-2-carboxylic

Se disolvio acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}tiofeno-2-carboxilico 19d (1,3 g, 2,83 mmol) en 40 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con etanolamina (344 mg, 5,65 mmol) para formar una solucion de color purpura, y se agito durante 2 horas a temperatura ambiente. Una gran cantidad de solido se precipito en la solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(etanolamina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-fenil}-tiofeno-2-carboxilico 19 (1,513 g, rendimiento: 92,0%) en forma de un solido de color rojo intenso. HPLC: 98,65% EM m/z (IEN): 458,7 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,94 (s, 1H), 7,88 (s, 1H), 7,68 (s, 1H), 7,55-7,59 (m, 2H), 7,28-7,30 (m, 1H), 7,22 (d, Acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) - hydrazino] -phenyl} thiophene-2-carboxylic acid 19d (1.3 g, 2.83 mmol) in 40 ml of tetrahydrofuran to form a red suspension intense. The reaction mixture was added with ethanolamine (344 mg, 5.65 mmol) to form a color solution. purple, and stirred for 2 hours at room temperature. A large amount of solid precipitated into the solution, was filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the compound of the title bis- (ethanolamine) of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazole -4-ylidene) hydrazino] -phenyl} -thiophene-2-carboxylic 19 (1,513 g, yield: 92.0%) as an intense red solid. HPLC: 98.65% MS m / z (ESI): 458.7 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.94 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.55-7.59 (m, 2H), 7.28-7.30 (m, 1H), 7.22 (d,

J = 8,4 Hz, 1H), 6,83 (t, J = 8,0 Hz, 3H), 3,65-3,68 (m, 4H), 2,88-2,92 (m, 8H), 2,38 (s, 3H), 2,06-2,14 (m, 2H) Ejemplo 20: bis-(dietilamina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-fenil}-tiofeno-2-carboxilico J = 8.4 Hz, 1H), 6.83 (t, J = 8.0 Hz, 3H), 3.65-3.68 (m, 4H), 2.88-2.92 (m, 8H ), 2.38 (s, 3H), 2.06-2.14 (m, 2H) Example 20: bis- (diethylamine) of the acid (Z) -4- {2-hydroxy-3- [N'- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) hydrazino] -phenyl} -thiophene-2-carboxylic acid

Se disolvio acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}tiofeno-2-carboxilico 19d (150 mg, 0,33 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio gota a gota con dietilamina (49 mg, 0,66 mmol) para formar una solucion de color purpura, y se agito durante 2 horas a temperatura ambiente. El solido se precipito en una solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(dietilamina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-fenil}-tiofeno-2-carboxilico 20 (157 mg, en forma de un solido de color rojo intenso). Rendimiento: 79,3%. HPLC: 98,98% EM m/z (IEN): 458,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,81(s, 1H), 7,73 (s, 1H), 7,68-7,70 (m, 2H), 7,62 (d, J = 8,8 Hz, 1H), 7,22-7,26 (m, 2H), 7,06 (t, J = 8,0 Hz, 1H), 3,03 (c, J = 7,2 Hz, 8H), 2,90-2,97 (m, 4H), 2,37 (s, 3H), 2,07-2,15 (m, 2H), 1,29 (t, J = 7,2 Hz, 12H) Acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) - hydrazino] -phenyl} thiophene-2-carboxylic acid 19d (150 mg, 0.33 mmol) in 5 ml of tetrahydrofuran to form a red suspension intense. The reaction mixture was added dropwise with diethylamine (49 mg, 0.66 mmol) to form a solution. purple in color, and stirred for 2 hours at room temperature. The solid precipitated into a solution, was filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the compound of the bis- (diethylamine) title of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazole- 4-ylidene) hydrazino] -phenyl} -thiophene-2-carboxylic 20 (157 mg, in the form of an intense red solid). Yield: 79.3%. HPLC: 98.98% MS m / z (ESI): 458.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.81 (s, 1H), 7.73 (s, 1H), 7.68-7.70 (m, 2H), 7.62 (d, J = 8 , 8 Hz, 1H), 7.22-7.26 (m, 2H), 7.06 (t, J = 8.0 Hz, 1H), 3.03 (c, J = 7.2 Hz, 8H), 2.90-2.97 (m, 4H), 2, 37 (s, 3H), 2.07-2.15 (m, 2H), 1.29 (t, J = 7.2 Hz, 12H)

Ejemplo 21: bis-(piperazina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)hidrazino]-fenil}-tiofeno-2-carboxilico Example 21: bis- (piperazine) of the acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene) hydrazino] -phenyl} -thiophene-2-carboxylic

Se disolvio acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}tiofeno-2-carboxilico 19d (150 mg, 0,33 mmol) en 5 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con piperazina (56 mg, 0,65 mmol) para formar una solucion de color purpura, y se agito durante 2 horas a temperatura ambiente. El solido se precipito en una solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis(piperazina) del acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5-dihidro-pirazol-4-ilideno)-hidrazino]-fenil}tiofeno-2-carboxilico 21 (195 mg, rendimiento: 94,7%) en forma de un solido de color rojo intenso. HPLC: 98,17% EM m/z (IEN): 458,8 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,85 (s, 1H), 7,75 (s, 1H), 7,71 (s, 1H), 7,62 (m, 2H), 7,26 (m, 2H), 6,95 (t, 1H), 2,96 (m, 16H), 2,91 (m, 4H), 2,37 (s, 3H), 2,11 (m, 2H) Acid (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) - hydrazino] -phenyl} thiophene-2-carboxylic acid 19d (150 mg, 0.33 mmol) in 5 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with piperazine (56 mg, 0.65 mmol) to form a purple solution, and stirred for 2 hours at room temperature. The solid was precipitated in a solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis (piperazine) of the acid (Z) -4- { 2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -phenyl} thiophene-2-carboxylic acid 21 (195 mg, yield: 94.7%) in the form of an intense red solid. HPLC: 98.17% MS m / z (ESI): 458.8 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.85 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.62 (m, 2H), 7.26 (m, 2H), 6.95 (t, 1H), 2.96 (m, 16H), 2.91 (m , 4H), 2.37 (s, 3H), 2.11 (m, 2H)

Ejemplo 22: bis-(etanolamina) del acido (Z)-4-(2-Hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftal-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Etapa 1 Example 22: bis- (ethanolamine) of the acid (Z) -4- (2-Hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphtal) -2-yl) -1,5-dihydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic Stage 1

Acido 4-bromo-furan-2-carboxilico 4-Bromo-furan-2-carboxylic acid

Se afadio una mezcla de acido 4,5-dibromo-furan-2-carboxilico 22a (5,5 g, 20,3 mmol) y 18 ml de hidroxido de amonio a 63 ml de agua seguido de la adicion de polvo de cinc (1,46 g, 22,33 mmol). Despues de que se completara la adicion, la mezcla de reaccion se agito a temperatura ambiente durante 6 horas. La mezcla se ajusto a pH 3 con acido clorhidrico 1 M para formar una gran cantidad de precipitados. La mezcla se filtro y la torta de filtro se lavo con n-hexano (15 ml x 4) y se seco para obtener el compuesto del titulo acido 4-bromo-furan-2-carboxilico 22b (3,2 g, rendimiento del 83,1%) en forma de un solido de color blanco. EM m/z (IEN): 188,7 [M-1] A mixture of 4,5-dibromo-furan-2-carboxylic acid 22a (5.5 g, 20.3 mmol) and 18 ml of ammonium hydroxide was added to 63 ml of water followed by the addition of zinc powder ( 1.46 g, 22.33 mmol). After the addition was completed, the reaction mixture was stirred at room temperature for 6 hours. The mixture was adjusted to pH 3 with 1 M hydrochloric acid to form a large amount of precipitates. The mixture was filtered and the filter cake was washed with n-hexane (15 ml x 4) and dried to obtain the title compound 4-bromo-furan-2-carboxylic acid 22b (3.2 g, 83 yield , 1%) in the form of a white solid. MS m / z (ESI): 188.7 [M-1]

Etapa 2 Stage 2

Acido 4-(3-nitro-2-metoxi-fenil)-furan-2-carboxilico 4- (3-Nitro-2-methoxy-phenyl) -furan-2-carboxylic acid

Se disolvieron 2-(2-metoxi-3-nitro-fenil)-4,4,5,5-tetrametil-1 ,3,2-dioxaborolano 4d (4 g, 14,34 mmol), acido 4-bromofuran-2-carboxilico 22b (2,18 g, 11,47 mmol), tetraquis(trifenilfosfina)paladio (829 mg, 0,717 mmol) y carbonato potasico (3,96 g, 28,68 mmol) en la mezcla de disolvente de 80 ml de 1,4-dioxano y 30 ml de agua. La mezcla de reaccion se calento a reflujo durante 2,5 horas. La mezcla se ajusto a pH 3 con acido clorhidrico 1 M y despues se extrajo con acetato de etilo (80 ml x 3). Los extractos organicos combinados se concentraron a presion reducida. El residuo se purifico por cromatografia en columna sobre gel de silice para obtener el compuesto del titulo acido 4-(3nitro-2-metoxi-fenil)-furan-2-carboxilico 22c (3,42 g, rendimiento del 90,7%) en forma de un aceite de color pardo. EM m/z (IEN): 261,8 [M-1] 2- (2-Methoxy-3-nitro-phenyl) -4,4,5,5-tetramethyl-1, 3,2-dioxaborolane 4d (4 g, 14.34 mmol), 4-bromofuran-2 acid were dissolved -carboxylic 22b (2.18 g, 11.47 mmol), tetrakis (triphenylphosphine) palladium (829 mg, 0.717 mmol) and potassium carbonate (3.96 g, 28.68 mmol) in the 80 ml solvent mixture of 1,4-dioxane and 30 ml of water. The reaction mixture was heated at reflux for 2.5 hours. The mixture was adjusted to pH 3 with 1M hydrochloric acid and then extracted with ethyl acetate (80 ml x 3). The combined organic extracts were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain the title compound 4- (3-nitro-2-methoxy-phenyl) -furan-2-carboxylic acid 22c (3.42 g, 90.7% yield) in the form of a brown oil. MS m / z (ESI): 261.8 [M-1]

Etapa 3 Acido 4-(3-amino-2-metoxi-fenil)-furan-2-carboxilico Step 3 4- (3-Amino-2-methoxy-phenyl) -furan-2-carboxylic acid

Se disolvio acido 4-(3-nitro-2-metoxi-fenil)-furan-2-carboxilico 22c (500 mg, 1,9 mmol) en 15 ml de acetato de etilo seguido de la adicion de 100 mg de paladio sobre carbono y formiato amonico (429 mg, 7,6 mmol). La mezcla de reaccion se calento a reflujo durante 3 horas. La mezcla se filtro para retirar paladio sobre carbono y se concentro a presion reducida para obtener el compuesto del titulo acido 4-(3-amino-2-metoxi-fenil)-furan-2-carboxilico 22d (325 mg, rendimiento del 73,4%) en forma de un aceite de color amarillo. EM m/z (IEN): 231,8 [M-1] 4- (3-Nitro-2-methoxy-phenyl) -furan-2-carboxylic acid 22c (500 mg, 1.9 mmol) was dissolved in 15 ml of ethyl acetate followed by the addition of 100 mg of palladium on carbon and ammonium formate (429 mg, 7.6 mmol). The reaction mixture was heated at reflux for 3 hours. The mixture was filtered to remove palladium on carbon and concentrated under reduced pressure to obtain the title compound 4- (3-amino-2-methoxy-phenyl) -furan-2-carboxylic acid 22d (325 mg, yield 73, 4%) in the form of a yellow oil. MS m / z (ESI): 231.8 [M-1]

Etapa 4 Stage 4

Bromhidrato del acido 4-(3-amino-2-hidroxi-fenil)-furan-2-carboxilico 4- (3-Amino-2-hydroxy-phenyl) -furan-2-carboxylic acid hydrobromide

Se disolvio acido 4-(3-amino-2-metoxi-fenil)-furan-2-carboxilico 22d (325 mg, 1,4 mmol) en 5 ml de diclorometano seguido de la adicion gota a gota de tribromuro de boro (2,8 ml, 5,6 mmol). La mezcla se hizo reaccionar a temperatura ambiente durante 4,5 horas. Se afadieron 5 ml de metanol y despues la mezcla se concentro a presion reducida. El residuo se diluyo con 10 ml de acetato de etilo y se agito durante 0,5 horas. La mezcla se filtro y la torta de filtro se seco para obtener el compuesto del titulo bromhidrato del acido 4-(3-amino-2-hidroxi-fenil)-furan-2carboxilico 22e (174 mg, rendimiento del 57,1%) en forma de un solido de color gris. EM m/z (IEN): 217,7 [M-1] 4- (3-Amino-2-methoxy-phenyl) -furan-2-carboxylic acid 22d (325 mg, 1.4 mmol) was dissolved in 5 ml of dichloromethane followed by the dropwise addition of boron tribromide (2 , 8 ml, 5.6 mmol). The mixture was reacted at room temperature for 4.5 hours. 5 ml of methanol was added and then the mixture was concentrated under reduced pressure. The residue was diluted with 10 ml of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake dried to obtain the title compound 4- (3-amino-2-hydroxy-phenyl) -furan-2-carboxylic acid 22e (174 mg, 57.1% yield) in Shape of a gray solid. MS m / z (ESI): 217.7 [M-1]

Etapa 5 Stage 5

Acido (Z)-4-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftal-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}fenil)-furan-2-carboxilico (Z) -4- (2-Hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphtal-2-yl) -1.5 -dihydro-pyrazol-4-ylidene] -hydrazino} phenyl) -furan-2-carboxylic

Se disolvio acido 4-(3-amino-2-hidroxi-fenil)-furan-2-carboxilico 22e (170 mg, 0,57 mmol) en acido clorhidrico (1,9 ml, 1 M) tras la refrigeracion en un bafo de hielo-agua seguido de la adicion gota a gota de 0,7 ml de una solucion de nitrito sodico (43 mg, 0,63 mmol). Despues de que la mezcla se hiciera reaccionar durante 20 minutos, se afadio 5metil-2-(5,6,7,8-tetrahidro-naftalen-2-il)-2,4-dihidro-pirazol-3-ona 7c (116 mg, 0,51 mmol). La mezcla se ajusto a pH 8-9 con una solucion saturada de bicarbonato sodico seguido de la adicion de 2 ml de etanol. La mezcla se hizo reaccionar a temperatura ambiente durante 24 horas. La mezcla se filtro y despues a la torta de filtro se le afadieron 15 ml de agua. Despues de la refrigeracion en un bafo de hielo-agua, la mezcla se ajusto a pH 2-3 con acido clorhidrico concentrado y se filtro. La torta de filtro se lavo con acetato de etilo y se seco para obtener el compuesto del titulo acido (Z)-4-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftal-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 22f (13 mg, rendimiento del 5,5%) en forma de un solido de color rojo. EM m/z (IEN): 456,7 [M-1] 1H RMN (400 MHz, DMSO-d6): 8 13,75 (s a, 1H), 13,20 (s a, 1H), 9,68 (s a, 1H), 8,37 (s, 1H), 7,62-7,68 (m, 4H), 7,41-7,43 (m, 1H), 7,11-7,15 (m, 2H), 2,67-2,76 (m, 2H), 2,31 (s, 3H),1,75 (m, 4H) 4- (3-Amino-2-hydroxy-phenyl) -furan-2-carboxylic acid 22e (170 mg, 0.57 mmol) was dissolved in hydrochloric acid (1.9 ml, 1 M) after cooling in a bafo of ice-water followed by the dropwise addition of 0.7 ml of a solution of sodium nitrite (43 mg, 0.63 mmol). After the mixture was reacted for 20 minutes, 5-methyl-2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -2,4-dihydro-pyrazol-3-one 7c (116) was added mg, 0.51 mmol). The mixture was adjusted to pH 8-9 with a saturated sodium bicarbonate solution followed by the addition of 2 ml of ethanol. The mixture was reacted at room temperature for 24 hours. The mixture was filtered and then 15 ml of water was added to the filter cake. After cooling in an ice-water bath, the mixture was adjusted to pH 2-3 with concentrated hydrochloric acid and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound acid (Z) -4- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5 , 6,7,8-tetrahydro-naphtal-2-yl) -1,5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 22f (13 mg, 5.5% yield ) in the form of a solid red. MS m / z (ESI): 456.7 [M-1] 1H NMR (400 MHz, DMSO-d6): 8 13.75 (sa, 1H), 13.20 (sa, 1H), 9.68 ( sa, 1H), 8.37 (s, 1H), 7.62-7.68 (m, 4H), 7.41-7.43 (m, 1H), 7.11-7.15 (m, 2H), 2.67-2.76 (m, 2H), 2.31 (s, 3H), 1.75 (m, 4H)

Etapa 6 Stage 6

bis-(etanolamina) del acido (Z)-4-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftal-2-il)-1,5-di-hidro-pirazol-4ilideno]-hidrazino}-fenil)-furan-2-carboxilico bis- (ethanolamine) of the acid (Z) -4- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphtal-2- il) -1,5-di-hydro-pyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic acid

Se disolvio acido (Z)-4-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftal-2-il)-1,5-di-hidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico 22f (1,2 g, 2,6 mmol) en 20 ml de tetrahidrofurano para formar una suspension de color rojo intenso. La mezcla de reaccion se afadio con etanolamina (399 mg, 6,5 mmol) para formar una solucion de color purpura, y se agito durante 6 horas a temperatura ambiente. Una gran cantidad del solido se precipito en la solucion, se filtro, despues la torta de filtro se lavo con tetrahidrofurano (1 ml x 3) y se seco al vacio para obtener el compuesto del titulo bis-(etanolamina) del acido (Z)-4-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8tetrahidro-naftal-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico 22 (1,51 g, en forma de un solido de color rojo). Rendimiento del 72,8%. HPLC: 97,16% EM m/z (IEN): 456,7 [M-1] 1H RMN (400 MHz, CD3OD): 8 8,20 (s, 1H), 7,51-7,56 (m, 3H), 7,31-7,35 (m, 2H), 7,07 (d, J = 9,2 Hz, 1H), 6,89 (t, J = 8,0 Hz, 1H), 3,68-3,71 (m, 4H), 2,90-2,95 (m, 4H), 2,76-2,81 (m, 4H), 2,39 (s, 3H), 1,80-1,85 (m, 4H) Acid (Z) -4- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphtal-2-yl) -1 was dissolved , 5-di-hydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid 22f (1.2 g, 2.6 mmol) in 20 ml of tetrahydrofuran to form a deep red suspension. The reaction mixture was added with ethanolamine (399 mg, 6.5 mmol) to form a purple solution, and stirred for 6 hours at room temperature. A large amount of the solid was precipitated in the solution, filtered, then the filter cake was washed with tetrahydrofuran (1 ml x 3) and dried in vacuo to obtain the title compound bis- (ethanolamine) of the acid (Z) -4- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphtal-2-yl) -1,5-dihydro-pyrazol-4 -ilidene] -hydrazino} -phenyl) -furan-2-carboxylic 22 (1.51 g, in the form of a red solid). 72.8% yield. HPLC: 97.16% MS m / z (ESI): 456.7 [M-1] 1H NMR (400 MHz, CD3OD): 8.20 (s, 1H), 7.51-7.56 (m , 3H), 7.31-7.35 (m, 2H), 7.07 (d, J = 9.2 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H), 3 , 68-3.71 (m, 4H), 2.90-2.95 (m, 4H), 2.76-2.81 (m, 4H), 2.39 (s, 3H), 1.80 -1.85 (m, 4H)

Ejemplo 23: Colina del acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidropirazol-4-ilideno]-hidrazino}-fenil)-furan-2-carboxilico Example 23: Choline of acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl ) -1,5-dihydropyrazol-4-ylidene] -hydrazino} -phenyl) -furan-2-carboxylic

Se disolvio acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico (1,1 g, 2,4 mmol) en 19 ml del disolvente de la mezcla de acetato de etilo y etanol (v/v = 12:7), despues la mezcla de reaccion se calento a 40 °C y se agito durante 15 minutos para formar una suspension de color marron. La mezcla de reaccion se afadio lentamente con una solucion 1 M de colina en metanol (2,4 ml, 2,4 mmol) para formar una solucion de color negro hasta que el solido desaparecio. La solucion de reaccion se afadio con 1 ml de agua, despues se enfrio a 35 °C, se hizo reaccionar durante 3 horas y despues se agito durante 72 horas mas a temperatura ambiente. El solido de color naranja se precipito, se filtro, despues la torta de filtro se lavo con acetato de etilo (5 ml x 3) y se seco para obtener el compuesto del titulo colina del acido (Z)-5Acid (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1 was dissolved , 5-dihydro-pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic acid (1.1 g, 2.4 mmol) in 19 ml of the solvent of the mixture of ethyl acetate and ethanol (v / v = 12: 7), then the reaction mixture was heated to 40 ° C and stirred for 15 minutes to form a brown suspension. The reaction mixture was added slowly with a 1M solution of choline in methanol (2.4 ml, 2.4 mmol) to form a black solution until the solid disappeared. The reaction solution was added with 1 ml of water, then cooled to 35 ° C, reacted for 3 hours and then stirred for an additional 72 hours at room temperature. The orange solid precipitated, was filtered, then the filter cake was washed with ethyl acetate (5 ml x 3) and dried to obtain the title compound choline of the acid (Z) -5

5 (2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8-tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]-hidrazino}-fenil)-furan-2carboxilico (620 mg, rendimiento: 46,0%) en forma de un solido de color naranja. EM m/z (IEN): 456,7 [M-1] 1H RMN (400 MHz, CD3OD): 8 7,66-7,57 (m, 4H), 7,09-7,04 (m, 3H), 6,92 (d, J = 3,6 Hz, 1H), 4,03-3,99 (m, 2H), 3,51-3,48 (m, 2H), 3,22 (s, 9H), 2,81-2,75 (m, 4H), 2,33 (s, 3H), 1,83-1,81 (m, 4H). 5 (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro-pyrazol-4 -ilidene] -hydrazino} -phenyl) -furan-2-carboxylic acid (620 mg, yield: 46.0%) in the form of an orange solid. MS m / z (ESI): 456.7 [M-1] 1H NMR (400 MHz, CD3OD): 8 7.66-7.57 (m, 4H), 7.09-7.04 (m, 3H ), 6.92 (d, J = 3.6 Hz, 1H), 4.03-3.99 (m, 2H), 3.51-3.48 (m, 2H), 3.22 (s, 9H), 2.81-2.75 (m, 4H), 2.33 (s, 3H), 1.83-1.81 (m, 4H).

Ejemplo 24: Composicion de los Comprimidos Example 24: Composition of Tablets

La lactosa, celulosa microcristalina, almidon glicolato sodico, estearato de magnesio y el Compuesto del Ejemplo 7 se mezclan en las proporciones mostradas en la Tabla 1 que se indica a continuacion. Despues, la mezcla se 15 comprime en comprimidos. Lactose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate and the Compound of Example 7 are mixed in the proportions shown in Table 1 below. Then, the mixture is compressed into tablets.

Tabla 1 Table 1

INGREDIENTE mg Compuesto del Ejemplo 7 8,45 Celulosa microcristalina 112 INGREDIENT mg Compound of Example 7 8.45 Microcrystalline cellulose 112

Lactosa 70 Almidon glicolato sodico 8 Estearato de magnesio 2 Lactose 70 Sodium starch glycolate 8 Magnesium stearate 2

Ejemplo 25: Composicion Parenteral Inyectable Example 25: Injectable Parenteral Composition

Una forma inyectable para administrar el Compuesto del Ejemplo 7 se produce agitando 5,0 mg del compuesto en 1,0 ml de solucion salina normal. An injectable form for administering the Compound of Example 7 is produced by stirring 5.0 mg of the compound in 1.0 ml of normal saline.

Ejemplo de Prueba 25 Ensayo de Solubilidad Test Example 25 Solubility Test

De acuerdo con el procedimiento convencional para la determinacion de la solubilidad, la solubilidad de los compuestos de los Ejemplos y sus sales se ensayaron en tres sistemas diferentes: agua, acido clorhidrico al 0,1% y metanol. According to the conventional procedure for the determination of solubility, the solubility of the compounds of the Examples and their salts were tested in three different systems: water, 0.1% hydrochloric acid and methanol.

La solubilidad se caracterizo por: The solubility was characterized by:

La expresion "muy soluble" se refiere a que 1 g (ml) de soluto puede disolverse en menos de 1 ml de The term "very soluble" refers to the fact that 1 g (ml) of solute can be dissolved in less than 1 ml of

35 disolvente; La expresion "soluble libremente" se refiere a que 1 g (ml) de soluto puede disolverse en de 1 ml a 10 ml, sin incluir 10 ml de disolvente; El termino "soluble" se refiere a que 1 g (ml) de soluto puede disolverse en de 10 ml a 30 ml, sin incluir 30 ml de disolvente; La expresion "escasamente soluble" se refiere a que 1 g (ml) de soluto puede disolverse en de 30 ml a 100 ml, sin incluir 100 ml de disolvente; La expresion "ligeramente soluble" se refiere a que 1 g (ml) de soluto puede disolverse en de 100 ml a 1000 ml, sin incluir 1000 ml de disolvente; La expresion "muy ligeramente soluble" se refiere a que 1 g (ml) de soluto puede disolverse en de 1000 ml Solvent; The term "freely soluble" refers to that 1 g (ml) of solute can be dissolved in 1 ml to 10 ml, not including 10 ml of solvent; The term "soluble" refers to that 1 g (ml) of solute can be dissolved in 10 ml to 30 ml, not including 30 ml of solvent; The term "poorly soluble" refers to that 1 g (ml) of solute can be dissolved in 30 ml to 100 ml, not including 100 ml of solvent; The term "slightly soluble" refers to that 1 g (ml) of solute can be dissolved in 100 ml to 1000 ml, not including 1000 ml of solvent; The term "very slightly soluble" refers to the fact that 1 g (ml) of solute can be dissolved in 1000 ml

45 a 10000 ml, sin incluir 10000 ml de disolvente; La expresion "practicamente insoluble o insoluble" se refiere a que 1 g (ml) de soluto no puede disolverse por completo en 10000 ml de disolvente. 45 to 10,000 ml, not including 10,000 ml of solvent; The term "practically insoluble or insoluble" refers to the fact that 1 g (ml) of solute cannot be completely dissolved in 10,000 ml of solvent.

Los resultados de la solubilidad se mostraron como se indica a continuacion: El resultado mostro que en comparacion con el compuesto del Ejemplo 1j, Ejemplo 4h, Ejemplo 7d, Ejemplo 16a y el Ejemplo 19d, la solubilidad de sus sales obviamente aumento, especialmente en agua y metanol. Especialmente, las sales del Ejemplo 4 y el Ejemplo 7 tenian relativamente mejora solubilidad en acido clorhidrico al 0,1%, y las dos sales fueron muy ligeramente solubles, mientras que las demas eran practicamente insolubles o insolubles. The solubility results were shown as follows: The result showed that in comparison with the compound of Example 1j, Example 4h, Example 7d, Example 16a and Example 19d, the solubility of its salts obviously increased, especially in water and methanol. Especially, the salts of Example 4 and Example 7 had relatively improved solubility in 0.1% hydrochloric acid, and the two salts were very slightly soluble, while the others were practically insoluble or insoluble.

Ejemplo N° Example No.
Solubilidad (mg/ml) Solubility (mg / ml)

acido clorhidrico al 0,1% 0.1% hydrochloric acid
agua metanol Water methanol

1j 1j
<0,001 <0,001 <0,001 <0.001 <0.001 <0.001

1 one
<0,001 0,003 1,469 <0.001 0.003 1,469

3 3
<0,001 2,290 1,534 <0.001 2,290 1,534

4h 4h
<0,001 <0,001 <0,001 <0.001 <0.001 <0.001

4 4
0,024 2,905 19,001 0.024 2,905 19,001

6 6
<0,001 0,001 3,009 <0.001 0.001 3,009

7d 7d
<0,001 <0,001 <0,001 <0.001 <0.001 <0.001

7 7
0,029 3,960 22,377 0.029 3,960 22,377

8 8
<0,001 5,049 4,595 <0.001 5,049 4,595

9 9
<0,001 9,974 19,331 <0.001 9,974 19,331

10 10
<0,001 3,715 3,417 <0.001 3,715 3,417

11 eleven
<0,001 3,003 3,617 <0.001 3,003 3,617

12 12
<0,001 5,945 18,823 <0.001 5,945 18,823

13 13
<0,001 <0,001 15,432 <0.001 <0.001 15,432

14 14
<0,001 1,876 3,722 <0.001 1,876 3,722

15 fifteen
<0,001 0,645 3,023 <0.001 0.645 3,023

16a 16th
<0,001 <0,001 <0,001 <0.001 <0.001 <0.001

17 17
<0,001 2,000 5,849 <0.001 2,000 5,849

18 18
<0,001 2,741 6,096 <0.001 2,741 6,096

19d 19d
<0,001 <0,001 <0,001 <0.001 <0.001 <0.001

20 twenty
<0,001 0,068 2,221 <0.001 0.068 2,221

21 twenty-one
<0,001 0,814 2,416 <0.001 0.814 2,416

23 2. 3
<0,001 0,286 22,597 <0.001 0.286 22,597

La estructura de los Compuestos del Ejemplo 1j, Ejemplo 4h, Ejemplo 7d, Ejemplo 16a y el Ejemplo 19d se mostro como se indica a continuacion: The structure of the Compounds of Example 1j, Example 4h, Example 7d, Example 16a and Example 19d were shown as follows:

Ejemplo N° Example No.
Estructura Compuesto Structure Compound

1j 1j
acido (Z)-2'-hidroxi-3'-[N'-(1-indan-5-il-3-metil-5-carbonil-1,5dihidro-pirazol-4-ilideno)-hidrazino]-bifenil-3-carboxilico (Z) -2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-carbonyl-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -biphenyl- 3-carboxylic

4h 4h
acido (Z)-5-(3-{N'-[1-(3,3-dimetil-indan-5-il)-3-metil-5-oxo-1,5dihidro-pirazol-4-ilideno]-hidrazino}-2-hidroxi-fenil)-furan-2carboxilico (Z) -5- (3- {N '- [1- (3,3-dimethyl-indan-5-yl) -3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene] - hydrazino} -2-hydroxy-phenyl) -furan-2-carboxylic

7d 7d
acido (Z)-5-(2-hidroxi-3-{N'-[3-metil-5-oxo-1-(5,6,7,8tetrahidro-naftalen-2-il)-1,5-dihidro-pirazol-4-ilideno]hidrazino}-fenil)-furan-2-carboxilico (Z) -5- (2-hydroxy-3- {N '- [3-methyl-5-oxo-1- (5,6,7,8-tetrahydro-naphthalen-2-yl) -1,5-dihydro acid -pyrazol-4-ylidene] hydrazino} -phenyl) -furan-2-carboxylic

16a 16th
acido (Z)-5-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-furan-2-carboxilico (Z) -5- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -phenyl acid } -furan-2-carboxylic

19d 19d
acido (Z)-4-{2-hidroxi-3-[N'-(1-indan-5-il-3-metil-5-oxo-1,5dihidro-pirazol-4-ilideno)-hidrazino]-fenil}-tiofeno-2-carboxilico (Z) -4- {2-hydroxy-3- [N '- (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -phenyl acid } -thiophene-2-carboxylic

Ensayo de Higroscopicidad Hygroscopicity Test

Prueba de higroscopicidad de los compuestos de la presente divulgacion despues un reposo durante 48 horas 15 Protocolo: Hygroscopicity test of the compounds of the present disclosure after a rest for 48 hours 15 Protocol:

1. El frasco de pesadas de vidrio arido con un tapon (el diametro externo es de 50 mm, la altura es 15 mm) se puso a 25 °C ± 1 °C adecuadamente en una secadora termostatica (se puso una solucion saturada de sulfato de amonio en la parte inferior, la humedad era del 79%) el dia antes del ensayo, el peso exacto se 1. The arid glass heavy jar with a cap (the external diameter is 50 mm, the height is 15 mm) was placed at 25 ° C ± 1 ° C properly in a thermostatic dryer (a saturated sulfate solution was put of ammonium at the bottom, the humidity was 79%) the day before the test, the exact weight was

20 midio como (m1); 20 measured as (m1);

2. 2.
El frasco de pesadas anterior se cubrio con los compuestos de la invencion (aproximadamente 1 g), y el espesor de los compuestos fue generalmente de 1 mm, el peso exacto se midio como (m2); The previous weighing bottle was covered with the compounds of the invention (approximately 1 g), and the thickness of the compounds was generally 1 mm, the exact weight was measured as (m2);

3. 3.
La boca del frasco de pesadas se mantuvo abierto y se coloco con el tapon en las condiciones anteriores con temperatura y humedad constantes durante 48 horas; The mouth of the heavy bottle was kept open and placed with the cap in the above conditions with constant temperature and humidity for 48 hours;

5 4. Se puso el tapon de nuevo en la botella, el peso exacto se midio como (m3) m -m 5 4. The cap was put back in the bottle, the exact weight was measured as (m3) m -m

3 2 3 2

Porcentaje de ganancia de peso = m2-m1 El grado de higroscopicidad se definio como se indica a continuacion: Deliquescer: Se vuelve liquido absorbiendo suficiente humedad. Alta higroscopicidad: el porcentaje de ganancia de peso por higroscopicidad no es menor del 15%. Weight gain percentage = m2-m1 The degree of hygroscopicity was defined as follows: Deliquescer: It becomes liquid absorbing enough moisture. High hygroscopicity: the percentage of weight gain due to hygroscopicity is not less than 15%.

15 Higroscopicidad: el porcentaje de ganancia de peso por higroscopicidad es menor del 15%, pero no inferior del 2%. Escasa higroscopicidad: el porcentaje de ganancia de peso por higroscopicidad es menor del 2%, pero no menor del 0,2%. Sin higroscopicidad o casi sin higroscopicidad: el porcentaje de ganancia de peso por higroscopicidad es menor del 15 Hygroscopicity: the percentage of weight gain due to hygroscopicity is less than 15%, but not less than 2%. Low hygroscopicity: the percentage of weight gain due to hygroscopicity is less than 2%, but not less than 0.2%. Without hygroscopicity or almost without hygroscopicity: the percentage of weight gain due to hygroscopicity is less than

0,2%. Los resultados de la higroscopicidad de los compuestos de la presente divulgacion se mostraron como se indica a continuacion: 0.2% The results of the hygroscopicity of the compounds of the present disclosure were shown as indicated by continuation:

Ejemplo N° Example No.
Porcentaje de ganancia de peso Higroscopicidad Weight gain percentage Hygroscopicity

7 7
1,2% Escasa higroscopicidad 1.2% Poor hygroscopicity

8 8
13,9% Higroscopicidad 13.9% Hygroscopicity

10 10
15,7% Alta higroscopicidad 15.7% High hygroscopicity

12 12
2,71% Higroscopicidad 2.71% Hygroscopicity

23 2. 3
8,48% Higroscopicidad 8.48% Hygroscopicity

Los resultados mostraron que en comparacion con las demas sales, la sal del Ejemplo 7, es decir, sal bis(etanolamina) del compuesto 7d, es menos higroscopica, y tenia mejora estabilidad en la humedad, lo que podria evitar los problemas potenciales del cambio de peso de los componentes activos durante la preparacion de capsulas The results showed that in comparison with the other salts, the salt of Example 7, that is, bis (ethanolamine) salt of compound 7d, is less hygroscopic, and had improved moisture stability, which could avoid the potential problems of change of weight of active components during capsule preparation

o comprimidos, es estable en gas, y es adecuada para la preparacion de una formulacion convencional y podria almacenarse a largo plazo. or tablets, is stable in gas, and is suitable for the preparation of a conventional formulation and could be stored in the long term.

ENSAYO BIOLOGICO BIOLOGICAL TEST

35 Ejemplo de Prueba 1: Efecto de la proliferacion de una serie de compuestos de TPO en una celula BAF3-TPOR. 35 Test Example 1: Effect of proliferation of a series of TPO compounds in a BAF3-TPOR cell.

1. Material y reactivos. 1. Material and reagents.

a) Medio RPMI 1640, polvo, 10 x 1 l, que contiene HEPES (Gibco, Catalogo N° 23400021). b) Suero Fetal Bovino (Gibco, Catalogo N° 10099-141). c) PENICILINA ESTREPTOMICINA SOL (Gibco, Catalogo N° 15140-122). d) Geneticina (G418) (Gibco, Catalogo N° 11811-098). e) IL-3 de raton recombinante (chemicon, Catalogo N° IL015). f) Mab de trombopoyetina R humana (TPO) (R&D, Catalogo N° MAB1016). a) RPMI 1640 medium, powder, 10 x 1 l, containing HEPES (Gibco, Catalog No. 23400021). b) Fetal Bovine Serum (Gibco, Catalog No. 10099-141). c) SOL STREPTOMYCIN PENICILLIN (Gibco, Catalog No. 15140-122). d) Geneticin (G418) (Gibco, Catalog No. 11811-098). e) Recombinant mouse IL-3 (chemicon, Catalog No. IL015). f) Human thrombopoietin R (TPO) Mab (R&D, Catalog No. MAB1016).

45 g) DMSO (AppliChem, Catalogo N° A3672). h) Kit de Mutagenesis Dirigida a Multiples Sitios QuikChange®, 10 Realizaciones (Stratagene ST200515). i) Cell Counting Kit-8 (Dojindo, Catalogo N° CK04-13) j) Celula BaF3 (Union cell culture center, Catalogo N° 0095) k) EX-EGFP-M02 (FulenGen, Catalogo N° EX- EGFP-M02 Control) l) EX-B0010-M02 (FulenGen, Catalogo N° EX-B0010-M02) 45 g) DMSO (AppliChem, Catalog No. A3672). h) QuikChange® Multiple Site Mutagenesis Kit, 10 Embodiments (Stratagene ST200515). i) Cell Counting Kit-8 (Dojindo, Catalog No. CK04-13) j) Cell BaF3 (Union cell culture center, Catalog No. 0095) k) EX-EGFP-M02 (FulenGen, Catalog No. EX- EGFP-M02 Control) l) EX-B0010-M02 (FulenGen, Catalog No. EX-B0010-M02)

2. Proceso operativo: 2. Operational process:

55 (1) Construcciones plasmidicas: En base a la informacion de secuencia del receptor de TPO (TPOR) de Entrez (Gene ID: 4325, Refseq: NM 005373), la mutacion de sitio dual se realizo en el plasmido EX-B0010-M02 usando el Kit de Mutagenesis Dirigida a Multiples Sitios QuikChange(R) (Stratagene). La secuencia de cebadores que contenian multiples sitios de mutacion se disefo como se indica a continuacion: 55 (1) Plasmid constructs: Based on the sequence information of the TPO receptor (TPOR) from Entrez (Gene ID: 4325, Refseq: NM 005373), the dual site mutation was performed in plasmid EX-B0010-M02 using the QuikChange (R) Multiple Straight Mutagenesis Kit (Stratagene). The sequence of primers containing multiple mutation sites was designed as follows:

5 g491 a: 5'-gggaacttcagatcagctgggaggagccg-3' g491a antisentido: 5'-cggctcctcccagctgatctgaagttccc-3'; c965t: 5'-caggaccatgctagctcccaaggcttcttct-3', c965t antisentido: 5'-agaagaagccttgggagctagcatggtcctg-3'. 5 g491 a: 5'-gggaacttcagatcagctgggaggagccg-3 ' antisense g491a: 5'-cggctcctcccagctgatctgaagttccc-3 '; c965t: 5'-caggaccatgctagctcccaaggcttcttct-3 ', c965t antisense: 5'-agaagaagccttgggagctagcatggtcctg-3 '.

10 Las celulas competentes de E. coli DH5a se transformaron con un plasmido mutado, y las colonias positivas se recogieron a traves de la seleccion de ampicilina. El resultado de la mutacion se confirmo por analisis de la secuencia. 10 The competent E. coli DH5a cells were transformed with a mutated plasmid, and the positive colonies were collected through the ampicillin selection. The result of the mutation was confirmed by sequence analysis.

(2) Linea celular transfectada estable BAF3-TPOR: El siguiente procedimiento se uso para construir la (2) BAF3-TPOR stable transfected cell line: The following procedure was used to construct the

15 celula BaF3 que sobreexpreso de forma estable el TPOR humana funcional. El plasmido EX-B0010-M02 mutado con exito (25 !g) que expreso el TPOR humano y el gen neomicina de deteccion se transfecto en celulas BaF3 de tipo natural (1 x 107) por electroporacion a 250 V durante 18 ms usando un generador de pulsos electrico (Electro Square Porator ECM830, BTX Division of Genetronic, Inc. Estados Unidos). Las celulas transfectadas estables BAF3-TPOR se seleccionaron con G418 (Gibco, Estados Unidos), despues 15 BaF3 cell that stably overexpressed functional human TPOR. Successfully mutated EX-B0010-M02 plasmid (25 µg) that expressed human TPOR and the detection neomycin gene was transfected into wild-type BaF3 cells (1 x 107) by electroporation at 250 V for 18 ms using a generator of electric pulses (Electro Square Porator ECM830, BTX Division of Genetronic, Inc. United States). BAF3-TPOR stable transfected cells were selected with G418 (Gibco, United States), after

20 se incubaron en medio RPMI1640 mas FBS al 10% (Gibco, Estados Unidos), 800 ng/ml de G418, 5 ng/ml, rmIL-3 (Chemicon, Estados Unidos). 20 were incubated in RPMI1640 medium plus 10% FBS (Gibco, United States), 800 ng / ml of G418, 5 ng / ml, rmIL-3 (Chemicon, United States).

3. Ensayo de compuestos de deteccion 3. Test of detection compounds

25 (1) Lavado de celulas por centrifugacion: Una cantidad adecuada de suspension celular se centrifugo a 1000 rpm durante 5 minutos, y el sobrenadante se desecho. Se afadieron 10 ml de medio de cultivo celular sin IL-3. Despues, la suspension celular resultante se centrifugo a 1000 rpm durante 5 minutos, y el sobrenadante se desecho. 25 (1) Washing of cells by centrifugation: An adequate amount of cell suspension was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 10 ml of cell culture medium without IL-3 was added. Then, the resulting cell suspension was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded.

(2) Se afadio 1 ml de medio de cultivo celular sin IL-3 para su igualacion, y se conto el numero de una 30 cantidad adecuada de suspension celular despues de la dilucion. (2) 1 ml of cell culture medium without IL-3 was added for equalization, and the number of an adequate amount of cell suspension was counted after dilution.

(3) (3)
De acuerdo con el resultado del recuento celular, se preparo una suspension celular en una concentracion de 100.000 celulas/ml. According to the result of the cell count, a cell suspension was prepared in a concentration of 100,000 cells / ml.

(4) (4)
Se transfirieron 100 !l de suspension celular a cada pocillo de la placa de cultivo de 96 pocillos, y hubo 100 µl of cell suspension was transferred to each well of the 96-well culture plate, and there was

3 pocillos paralelos, es decir, hubo un grupo de control en blanco (B), un grupo de control negativo (N), un 35 grupo de control positivo de TPO (P) y un grupo de compuesto de prueba (S). 3 parallel wells, that is, there was a blank control group (B), a negative control group (N), a positive TPO control group (P) and a test compound group (S).

(5) El compuesto de prueba se disolvio en DMSO para preparar una solucion madre 10 mM, y despues la solucion se diluyo con medio RPMI 1640 en una serie de muestras de prueba a diferente concentracion: 30 !M, 10 !M, 3 !M, 1 !M, 0,3 !M, 0,1 !M, 0,03 !M, 0,01 !M, 0,003 !M, 0,001 !M. (5) The test compound was dissolved in DMSO to prepare a 10 mM stock solution, and then the solution was diluted with RPMI 1640 medium in a series of test samples at different concentrations: 30 µM, 10 µM, 3! M, 1! M, 0.3! M, 0.1! M, 0.03! M, 0.01! M, 0.003! M, 0.001! M.

(6) (6)
Se transfirieron 10 !l de compuesto de prueba a cada pocillo respectivamente; al pocillo de control 40 positivo se le afadio 1 !l de rhTPO (10 !g/ml). 10 µl of test compound was transferred to each well respectively; 1 µl of rhTPO (10 µg / ml) was added to the positive control well 40.

(7)(7)
Las placas se incubaron en una incubadora en CO2 al 5% y a 37 °C durante 24 horas.  The plates were incubated in a 5% CO2 incubator and at 37 ° C for 24 hours.

(8) (8)
Despues de la incubacion, a cada pocillo se le afadieron 10 !l de solucion CCK-8 y las placas se incubaron en la incubadora durante 24 horas mas. After incubation, 10 µl of CCK-8 solution was added to each well and the plates were incubated in the incubator for an additional 24 hours.

(9)(9)
El valor DO se detecto a 450 nm por el lector de placas VICTOR3 (Perkin Elmer 1420-120). 45  The OD value was detected at 450 nm by the VICTOR3 plate reader (Perkin Elmer 1420-120). Four. Five

4. Calculo Analitico 4. Analytical Calculation

(1) La tasa de proliferacion se calculo como se indica a continuacion: (1) The proliferation rate was calculated as follows:

50 Tasa = [(S-B)/(P-B)] x 100% 50 Rate = [(S-B) / (P-B)] x 100%

S: Valor DO de los pocillos que contienen el compuesto de prueba. S: OD value of the wells containing the test compound.

B: Valor DO de los pocillos de control en blanco B: OD value of blank control wells

P: Valor DO de los pocillos de control positivos 55 (2) El valor EC50 se calculo mediante el softtare Origin 7.0. P: OD value of the positive control wells 55 (2) The EC50 value was calculated using the Origin 7.0 softtare.

5. Resultados: EC50 de la actividad de TPO de los compuestos de la presente divulgacion 5. Results: EC50 of the TPO activity of the compounds of the present disclosure

Ejemplo Example
EC50 EC50

Eltrombopag Eltrombopag
299 299

1j 1j
200 200

1 one
150 150

4h 4h
32 32

4 4
25 25

Ejemplo Example
EC50 EC50

5 5
19 19

6 6
36 36

7d 7d
21 twenty-one

7 7
19 19

8 8
4.4 4.4

9 9
14 14

10 10
16 16

11 eleven
21 twenty-one

12 12
14 14

13 13
20 twenty

14 14
19 19

15 fifteen
16 16

16a 16th
100 100

16 16
18 18

17 17
55 55

18 18
29 29

19d 19d
43 43

19 19
37 37

20 twenty
51 51

21 twenty-one
116 116

22f 22f
42 42

22 22
39 39

23 2. 3
43 43

Los resultados del estudio mostraron que en comparacion con el acido libre, las sales de la presente divulgacion tenian efectos de proliferacion mas fuertes con respecto a la celula BAF3-TPOR. El orden fue como se indica a continuacion: sales de la presente divulgacion � acido libre � Eltrombopag, y la actividad de las sales de la presente The results of the study showed that in comparison with the free acid, the salts of the present disclosure had stronger proliferation effects with respect to the BAF3-TPOR cell. The order was as follows: salts of the present disclosure � free acid � Eltrombopag, and the activity of the salts of the present

5 divulgacion eran mas activas que Eltrombopag. 5 disclosures were more active than Eltrombopag.

ENSAYO DE LA FARMACOCIN�TICA PHARMACOCINETIC TEST

Ejemplo de Prueba 1: Ensayo de farmacocinetica de los compuestos de la presente divulgacion en ratas 10 Test Example 1: Pharmacokinetic test of the compounds of the present disclosure in rats 10

1. Fin 1. End

Los compuestos de la presente divulgacion se administraron por via intragastrica a las ratas para determinar la concentracion de farmaco en plasma en diferentes puntos de tiempo por HPLC-UV. La conducta farmacocinetica de 15 los compuestos de la presente divulgacion se estudio y se evaluo en ratas. The compounds of the present disclosure were administered intragastrically to the rats to determine plasma drug concentration at different time points by HPLC-UV. The pharmacokinetic behavior of the compounds of the present disclosure was studied and evaluated in rats.

2. Protocolo 2. Protocol

2.1 Muestras 2.1 Samples

20 Compuestos del Ejemplo 1j, Ejemplo 1-3, Ejemplo 4h, Ejemplo 4, Ejemplo 5, Ejemplo 6, Ejemplo 7d, Ejemplo 7-15, Ejemplo 16a, Ejemplo 16-18, Ejemplo 19d, Ejemplo 19, Ejemplo 20, Ejemplo 21, Ejemplo 22f, Ejemplo 22 y Ejemplo 20 Compounds of Example 1j, Example 1-3, Example 4h, Example 4, Example 5, Example 6, Example 7d, Example 7-15, Example 16a, Example 16-18, Example 19d, Example 19, Example 20, Example 21 , Example 22f, Example 22 and Example

23. 2. 3.

25 2.2 Animales experimentales 25 2.2 Experimental animals

Se adquirieron ratas SD adultas sanas, machos y hembras por igual, en SINO-BRITSH SIPPR/BK LAB.ANIMAL LTD., CO, Licencia numero: SCXK (Shangai) 2003-0002 Healthy adult male and female SD rats were purchased equally, at SINO-BRITSH SIPPR / BK LAB.ANIMAL LTD., CO, License number: SCXK (Shanghai) 2003-0002

30 2.3 Instrumento Cromatografo liquido de alto rendimiento Waters 2695-2996, Waters Corp., Estados Unidos; 30 2.3 Instrument High performance liquid chromatograph Waters 2695-2996, Waters Corp., United States;

2.4 Preparacion de compuestos de prueba 2.4 Preparation of test compounds

35 El compuesto de prueba se diluyo con carboximetil celulosa sodica al 1% en 5 mg/ml (calculado como la forma de acido libre) de suspension antes de su uso. The test compound was diluted with 1% sodium carboxymethyl cellulose in 5 mg / ml (calculated as the free acid form) suspension before use.

2.5 Administracion 40 Las ratas SD adultas sanas, machos y hembras por igual, se dividieron en 23 grupos. Despues del ayuno durante una noche, a las ratas se les administro por via intragastrica una dosis de 50,0 mg/kg (calculado como la forma de acido libre), a un volumen de 10 ml/kg. 2.5 Administration 40 Healthy adult male and female SD rats were equally divided into 23 groups. After fasting overnight, the rats were administered intragastrically at a dose of 50.0 mg / kg (calculated as the free acid form), at a volume of 10 ml / kg.

2.6 Recogida de Muestras 2.6 Sample Collection

Se tomaron muestras de sangre (0,2 ml) de la cuenca ocular en una administracion previa y 0,5, 1,0, 2,0, 3,0, 4,0, 5,0, 6,0, 8,0, 11,0, 14,0, 24,0, 36,0 y 48,0 horas despues de la administracion, que se almacenaron en tubos heparinizados y se centrifugaron durante 10 minutos a 3.500 rpm. Las muestras de plasma se almacenaron a -20 °C hasta su analisis. Las ratas se alimentaron 2 horas despues de la administracion. Blood samples (0.2 ml) were taken from the eye socket in a previous administration and 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8, 0, 11.0, 14.0, 24.0, 36.0 and 48.0 hours after administration, which were stored in heparinized tubes and centrifuged for 10 minutes at 3,500 rpm. Plasma samples were stored at -20 ° C until analysis. The rats were fed 2 hours after administration.

2.7 Procedimientos Analiticos 2.7 Analytical Procedures

Se mezclaron bien 50 !l de plasma de rata, obtenido en diversos puntos de tiempo despues de la administracion, 50 !l de solucion convencional interna y 20 !l de una mezcla de disolvente de metanol y agua (80:20, v/v), y despues se afadieron 100 !l de para dar como resultado la precipitacion de proteinas. Despues, la mezcla se mezclo durante 3 minutos usando un agitador vorticial y se centrifugo durante 10 minutos a 13.500 rpm. Se analizaron 40 !l del sobrenadante por HPLC-UV. 50 µl of rat plasma, obtained at various time points after administration, 50 µl of conventional internal solution and 20 µl of a mixture of methanol solvent and water (80:20, v / v) were mixed well ), and then 100 µl of was added to result in protein precipitation. Then, the mixture was mixed for 3 minutes using a vortex shaker and centrifuged for 10 minutes at 13,500 rpm. 40 µl of the supernatant was analyzed by HPLC-UV.

2.82.8
Calculo de los Parametros Farmacocineticos  Calculation of Pharmacokinetic Parameters

El modelo compartimental de la farmacocinetica se ajusto para los compuestos de prueba y se calcularon los parametros farmacocineticos principales, en los que Cmax y tmax fueron los valores medidos realmente. The pharmacokinetic compartment model was adjusted for the test compounds and the main pharmacokinetic parameters were calculated, in which Cmax and tmax were the values actually measured.

3.3.
Resultados de los Parametros Farmacocineticos  Results of Pharmacokinetic Parameters

Los parametros farmacocineticos de los compuestos de la presente divulgacion se mostraron como se indica a continuacion: The pharmacokinetic parameters of the compounds of the present disclosure were shown as follows:

Numero Number
Ensayo de la Farmacocinetica (50 mg/kg) Pharmacokinetic Assay (50 mg / kg)

Conc. Plasma Conc. Plasma
Tiempo a Pico Area Bajo la Curva Semivida Tiempo de Residencia Medio Aclaramiento Volumen de Distribucion Aparente Weather to Pico Area down the curve Half-life Average Residence Time Clearing Apparent Distribution Volume

Cmax (!g/ml) Cmax (! G / ml)
Tmax (h) ABC (!g/ml x h) t1/2 (h) TRM (h) CL/F (l/h/kg) Vz/F (l/kg) Tmax (h) ABC (! G / ml x h) t1 / 2 (h) TRM (h) CL / F (l / h / kg) Vz / F (l / kg)

Eltrombopag Eltrombopag
61,8 ± 18,7 5,5 ± 1,0 680 ± 255 7,82 ± 1,34 11,2 ± 2,6 0,089 ± 0,052 0,95 ± 0,42 61.8 ± 18.7 5.5 ± 1.0 680 ± 255 7.82 ± 1.34 11.2 ± 2.6 0.089 ± 0.052 0.95 ± 0.42

1j 1j
29,05 ± 11,44 4,00 ± 1,41 131 ± 47 4,21 ± 1,86 3,89 ± 1,78 0,049 ± 0,035 0,29 ± 0,18 29.05 ± 11.44 4.00 ± 1.41 131 ± 47 4.21 ± 1.86 3.89 ± 1.78 0.049 ± 0.035 0.29 ± 0.18

1 one
90,1 ± 35,3 3,25 ± 1,5 501 ± 178 5,39 ± 0,94 4,96 ± 1,16 0,098 ± 0,072 0,45 ± 0,32 90.1 ± 35.3 3.25 ± 1.5 501 ± 178 5.39 ± 0.94 4.96 ± 1.16 0.098 ± 0.072 0.45 ± 0.32

2 2
83,9 ± 11,2 5,0 ± 1,16 833 ± 64 9,55 ± 1,44 11,08 ± 0,76 0,06 ± 0,005 0,83 ± 0,16 83.9 ± 11.2 5.0 ± 1.16 833 ± 64 9.55 ± 1.44 11.08 ± 0.76 0.06 ± 0.005 0.83 ± 0.16

3 3
79 ± 9,3 5,5 ± 1,0 842 ± 185 8,87 ± 0,78 13,0 ± 0,9 0,062 ± 0,013 0,78 ± 0,15 79 ± 9.3 5.5 ± 1.0 842 ± 185 8.87 ± 0.78 13.0 ± 0.9 0.062 ± 0.013 0.78 ± 0.15

4h 4h
1,29 ± 0,38 2,5 ± 1,0 9,5 ± 8,3 19,8 ± 16,4 31,7 ± 24,6 3,26 ± 1,93 83,4 ± 54,8 1.29 ± 0.38 2.5 ± 1.0 9.5 ± 8.3 19.8 ± 16.4 31.7 ± 24.6 3.26 ± 1.93 83.4 ± 54.8

4 4
2,32 ± 1,80 2,25 ± 2,47 19,0 ± 12,6 27,0 ± 31,5 38,3 ± 36,5 2,42 ± 1,60 58,1 ± 47,7 2.32 ± 1.80 2.25 ± 2.47 19.0 ± 12.6 27.0 ± 31.5 38.3 ± 36.5 2.42 ± 1.60 58.1 ± 47.7

5 5
19,8 ± 3,8 3,25 ± 1,5 255 ± 95 15,0 ± 6,2 20,8 ± 9,1 0,22 ± 0,07 4,23 ± 0,42 19.8 ± 3.8 3.25 ± 1.5 255 ± 95 15.0 ± 6.2 20.8 ± 9.1 0.22 ± 0.07 4.23 ± 0.42

6 6
13,0 ± 6,5 2,5 ± 1,0 175 ± 41 45,0 ± 70,3 60,4 ± 90,2 0,30 ± 0,084 16,0 ± 22,8 13.0 ± 6.5 2.5 ± 1.0 175 ± 41 45.0 ± 70.3 60.4 ± 90.2 0.30 ± 0.084 16.0 ± 22.8

7d 7d
16,2 ± 3,9 2,5 ± 1,0 132 ± 124 7,42 ± 7,19 11,0 ± 8,13 8,14 ± 8,44 36,1 ± 17,9 16.2 ± 3.9 2.5 ± 1.0 132 ± 124 7.42 ± 7.19 11.0 ± 8.13 8.14 ± 8.44 36.1 ± 17.9

7 7
74,1 ± 34,5 1,75 ± 0,5 469 ± 274 13,9 ± 6,07 13,3 ± 5,12 0,175 ± 0,169 2,48 ± 0,92 74.1 ± 34.5 1.75 ± 0.5 469 ± 274 13.9 ± 6.07 13.3 ± 5.12 0.175 ± 0.169 2.48 ± 0.92

8 8
36,2 ± 46,2 1,38 ± 1,11 352 ± 586 10,6 ± 9,02 12,1 ± 8,23 0,926 ± 1,013 8,55 ± 9,08 36.2 ± 46.2 1.38 ± 1.11 352 ± 586 10.6 ± 9.02 12.1 ± 8.23 0.926 ± 1.013 8.55 ± 9.08

9 9
21,2 ± 10,4 2,88 ± 2,59 146 ± 69,7 9,65 ± 2,48 10,5 ± 1,18 0,391 ± 0,145 5,15 ± 1,46 21.2 ± 10.4 2.88 ± 2.59 146 ± 69.7 9.65 ± 2.48 10.5 ± 1.18 0.391 ± 0.145 5.15 ± 1.46

10 10
65,6 ± 44,5 1,63 ± 0,75 381 ± 306 12,9 ± 6,32 11,5 ± 5,72 0,494 ± 0,754 4,54 ± 4,17 65.6 ± 44.5 1.63 ± 0.75 381 ± 306 12.9 ± 6.32 11.5 ± 5.72 0.494 ± 0.754 4.54 ± 4.17

11 eleven
40,2 ± 24,3 1,5 ± 0,58 270 ± 178 12,1 ± 7,19 10,0 ± 3,90 0,877 ± 1,465 5,80 ± 5,30 40.2 ± 24.3 1.5 ± 0.58 270 ± 178 12.1 ± 7.19 10.0 ± 3.90 0.877 ± 1.465 5.80 ± 5.30

12 12
17,8 ± 10,3 1,38 ± 1,11 58,5 ± 23,8 5,1 ± 2,41 5,87 ± 1,68 1,00 ± 0,504 6,35 ± 1,38 17.8 ± 10.3 1.38 ± 1.11 58.5 ± 23.8 5.1 ± 2.41 5.87 ± 1.68 1.00 ± 0.504 6.35 ± 1.38

13 13
8,10 ± 3,35 1,38 ± 1,11 42,8 ± 33,2 5,70 ± 2,50 8,05 ± 2,01 1,63 ± 0,83 14,9 ± 12,1 8.10 ± 3.35 1.38 ± 1.11 42.8 ± 33.2 5.70 ± 2.50 8.05 ± 2.01 1.63 ± 0.83 14.9 ± 12.1

14 14
17,8 ± 22,6 5,25 ± 1,5 132 ± 189 4,72 ± 2,82 7,20 ± 2,13 2,40 ± 2,41 9,54 ± 8,03 17.8 ± 22.6 5.25 ± 1.5 132 ± 189 4.72 ± 2.82 7.20 ± 2.13 2.40 ± 2.41 9.54 ± 8.03

15 fifteen
23,3 ± 13,6 2,0 ± 1,16 168 ± 118 6,56 ± 3,80 8,92 ± 2,04 0,758 ± 0,995 3,65 ± 1,79 23.3 ± 13.6 2.0 ± 1.16 168 ± 118 6.56 ± 3.80 8.92 ± 2.04 0.758 ± 0.995 3.65 ± 1.79

16a 16th
6,81 ± 6,23 2,75 ± 0,96 15,0 ± 17,2 1,82 ± 0,68 4,03 ± 2,55 2,98 ± 2,75 11,5 ± 7,5 6.81 ± 6.23 2.75 ± 0.96 15.0 ± 17.2 1.82 ± 0.68 4.03 ± 2.55 2.98 ± 2.75 11.5 ± 7.5

16 16
19,6 ± 16,3 2,00 ± 0,82 52,4 ± 48,0 2,08 ± 1,74 3,84 ± 1,03 1,94 ± 0,64 6,33 ± 4,57 19.6 ± 16.3 2.00 ± 0.82 52.4 ± 48.0 2.08 ± 1.74 3.84 ± 1.03 1.94 ± 0.64 6.33 ± 4.57

17 17
21,5 ± 10,5 3,38 ± 3,04 138 ± 33 12,7 ± 14,7 14,0 ± 12,0 0,38 ± 0,093 8,16 ± 11,09 21.5 ± 10.5 3.38 ± 3.04 138 ± 33 12.7 ± 14.7 14.0 ± 12.0 0.38 ± 0.093 8.16 ± 11.09

18 18
23,3 ± 11,6 1,63 ± 1,63 119 ± 102 3,99 ± 1,60 5,31 ± 2,64 0,63 ± 0,35 3,02 ± 1,01 23.3 ± 11.6 1.63 ± 1.63 119 ± 102 3.99 ± 1.60 5.31 ± 2.64 0.63 ± 0.35 3.02 ± 1.01

19d 19d
7,91 ± 6,84 2,50 ± 0,58 36,1 ± 36,4 1,84 ± 1,05 3,01 ± 1,99 1,44 ± 0,83 10,4 ± 8,4 7.91 ± 6.84 2.50 ± 0.58 36.1 ± 36.4 1.84 ± 1.05 3.01 ± 1.99 1.44 ± 0.83 10.4 ± 8.4

19 19
20,8 ± 17,3 1,81 ± 2,79 89,2 ± 7,2 5,71 ± 3,68 7,85 ± 2,92 0,88 ± 0,61 5,47 ± 2,72 20.8 ± 17.3 1.81 ± 2.79 89.2 ± 7.2 5.71 ± 3.68 7.85 ± 2.92 0.88 ± 0.61 5.47 ± 2.72

20 twenty
46,1 ± 15,7 4,5 ± 1,0 275 ± 116 7,24 ± 2,45 7,59 ± 1,33 0,21 ± 0,088 2,05 ± 0,68 46.1 ± 15.7 4.5 ± 1.0 275 ± 116 7.24 ± 2.45 7.59 ± 1.33 0.21 ± 0.088 2.05 ± 0.68

21 twenty-one
61,1 ± 1,38 5,5 ± 1,0 380 ± 109 6,86 ± 0,48 8,61 ± 0,31 0,14 ± 0,04 1,37 ± 0,32 61.1 ± 1.38 5.5 ± 1.0 380 ± 109 6.86 ± 0.48 8.61 ± 0.31 0.14 ± 0.04 1.37 ± 0.32

22f 22f
8,73 ± 2,58 4,25 ± 11,26 151 ± 97 9,21 ± 1,57 11,8 ± 4,5 0,69 ± 0,55 8,49 ± 2,16 8.73 ± 2.58 4.25 ± 11.26 151 ± 97 9.21 ± 1.57 11.8 ± 4.5 0.69 ± 0.55 8.49 ± 2.16

22 22
39,8 ± 18,2 5,0 ± 2,0 603 ± 240 9,95 ± 0,60 14,8 ± 1,0 0,24 ± 0,11 3,41 ± 1,75 39.8 ± 18.2 5.0 ± 2.0 603 ± 240 9.95 ± 0.60 14.8 ± 1.0 0.24 ± 0.11 3.41 ± 1.75

23 2. 3
17,2 ± 12,3 3,25 ± 3,18 123 ± 89,5 7,61 ± 1,34 11,7 ± 1,15 0,527 ± 0,24 5,52 ± 2,18 17.2 ± 12.3 3.25 ± 3.18 123 ± 89.5 7.61 ± 1.34 11.7 ± 1.15 0.527 ± 0.24 5.52 ± 2.18

Los resultados del estudio mostraron que despues de la administracion a ratas, en comparacion con el acido libre, la farmacocinetica y la biodisponibilidad de las sales de la presente divulgacion obviamente mejoro. Los datos farmacocineticos de la sal del Ejemplo 7, es decir, las sales bi-(monoetanolamina) del Ejemplo 7d, son mejores, y tenian buenas caracteristicas farmacocineticas. The results of the study showed that after administration to rats, in comparison with the free acid, the pharmacokinetics and the bioavailability of the salts of the present disclosure obviously improved. The pharmacokinetic data of the salt of Example 7, that is, the bi- (monoethanolamine) salts of Example 7d, are better, and had good pharmacokinetic characteristics.

Ejemplo de Prueba 2: Ensayo de la farmacocinetica de los compuestos de la presente divulgacion en perros Beagle Test Example 2: Pharmacokinetics test of the compounds of the present disclosure in Beagle dogs

1.one.
Fin  End

Los compuestos del Ejemplo 7, Ejemplo 8, Ejemplo 10 y Ejemplo 12 se administraron por via intragastrica a perros Beagle para determinar la concentracion del farmaco en plasma en diferentes puntos de tiempo por HPLC-UV. La conducta farmacocinetica de los compuestos de la presente divulgacion se estudio y se evaluo en perros Beagle. The compounds of Example 7, Example 8, Example 10 and Example 12 were administered intragastrically to Beagle dogs to determine the concentration of the drug in plasma at different time points by HPLC-UV. The pharmacokinetic behavior of the compounds of the present disclosure was studied and evaluated in Beagle dogs.

2.2.
Protocolo  Protocol

2.1 Muestras Compuestos del Ejemplo 7, Ejemplo 8, Ejemplo 10 y Ejemplo 12 2.1 Compound Samples of Example 7, Example 8, Example 10 and Example 12

2.2 Animales experimentales 2.2 Experimental animals

Se adquirieron 12 perros Beagles adultos sanos, macho, en Suzhou Xishan Drug Research and Development CO., LTD. Licencia numero: SCXK(Suzhou)2007-0005. 12 healthy adult male Beagles dogs were purchased from Suzhou Xishan Drug Research and Development CO., LTD. License number: SCXK (Suzhou) 2007-0005.

2.3 Instrumento Cromatografo liquido de alto rendimiento Agilent 1100, Agilent Corp., Estados Unidos. 2.3 Instrument High performance liquid chromatograph Agilent 1100, Agilent Corp., United States.

2.4 Preparacion de compuestos de prueba 2.4 Preparation of test compounds

El compuesto de prueba se diluyo con carboximetil celulosa sodica al 0,5% en 2,5 mg/ml (calculado como la forma de acido libre) de suspension antes de su uso. The test compound was diluted with 0.5% sodium carboxymethyl cellulose in 2.5 mg / ml (calculated as the free acid form) suspension before use.

2.5. Administracion 2.5 Administration

Los 12 perros Beagles adultos, sanos, macho, se dividieron en 4 grupos. Despues de una noche en ayuno, a los perros se les administro por via intragastrica una dosis de 5,0 mg/kg (calculado como la forma de acido libre), a un volumen de 2 ml/kg. The 12 adult, healthy, male Beagles dogs were divided into 4 groups. After a fasting night, the dogs were administered intragastrically a dose of 5.0 mg / kg (calculated as the free acid form), at a volume of 2 ml / kg.

2.6 Recogida de Muestras 2.6 Sample Collection

Se tomaron muestras de sangre (1,2 ml) de la vena de las patas delanteras previamente a la administracion y 0,25, 0,5, 1,0, 1,5, 2,0, 3,0, 5,0, 6,0, 8,0, 12,0, 14,0, 24,0 y 48,0 horas despues de la administracion, que se almacenaron en tubos heparinizados y se centrifugaron durante 10 minutos a 3.500 rpm. Las muestras de plasma se almacenaron a -20 °C hasta su analisis. Los perros Beagles se alimentaron 2 horas despues de la administracion. Blood samples (1.2 ml) were taken from the vein of the front legs prior to administration and 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 5.0 , 6.0, 8.0, 12.0, 14.0, 24.0 and 48.0 hours after administration, which were stored in heparinized tubes and centrifuged for 10 minutes at 3,500 rpm. Plasma samples were stored at -20 ° C until analysis. Beagles dogs were fed 2 hours after administration.

2.7 Procedimientos Analiticos 2.7 Analytical Procedures

Se afadieron 50 !l de plasma de perro Beagles, obtenido en diversos puntos de tiempo despues de la administracion, 20 !l de una solucion convencional interna y 150 !l de metanol para dar como resultado una precipitacion de proteinas. Despues, la mezcla se mezclo durante 1 minuto usando un agitador vorticial y se centrifugo durante 5 minutos a 11.000 rpm. Se analizaron 50 !l del sobrenadante por HPLC-UV. 50 µl of Beagles dog plasma, obtained at various time points after administration, 20 µl of a conventional internal solution and 150 µl of methanol were added to result in a precipitation of proteins. Then, the mixture was mixed for 1 minute using a vortex shaker and centrifuged for 5 minutes at 11,000 rpm. 50 µl of the supernatant was analyzed by HPLC-UV.

2.8 Calculo de los Parametros Farmacocineticos 2.8 Calculation of Pharmacokinetic Parameters

El modelo compartimental de la farmacocinetica se ajusto para los compuestos de prueba y se calcularon los parametros farmacocineticos principales, en los que Cmax y tmax fueron los valores medidos realmente. The pharmacokinetic compartment model was adjusted for the test compounds and the main pharmacokinetic parameters were calculated, in which Cmax and tmax were the values actually measured.

Numero Number
Ensayo de la Farmacocinetica (5 mg/kg) Pharmacokinetic Assay (5 mg / kg)

Conc. Plasma Conc. Plasma
Tiempo a Pico Area Bajo la Curva Semivida Tiempo de Residencia Medio Aclaramiento Volumen de Distribucion Aparente Weather to Pico Area down the curve Half-life Average Residence Time Clearing Apparent Distribution Volume

Cmax (!g/ml) Cmax (! G / ml)
Tmax (h) ABC (!g/ml x h) t1/2 (h) TRM (h) CL/F (l/h/kg) Vz/F (l/kg) Tmax (h) ABC (! G / ml x h) t1 / 2 (h) TRM (h) CL / F (l / h / kg) Vz / F (l / kg)

7 7
0,985 1,2 12,2 8,24 13,3 0,498 5,72 0.985 1.2 12.2 8.24 13.3 0.498 5.72

8 8
0,6 0,5 7,91 7,67 12,3 0,879 9,58 0.6 0.5 7.91 7.67 12.3 0.879 9.58

10 10
0,81 0,7 9,76 8,07 12,9 0,606 6,81 0.81 0.7 9.76 8.07 12.9 0.606 6.81

12 12
0,811 0,5 11,0 6,86 11,6 0,659 4,86 0.811 0.5 11.0 6.86 11.6 0.659 4.86

Los datos de las cuatro sales en el estudio actual mostraron que los compuestos del Ejemplo 7 eran obviamente superiores en la farmacocinetica. The data of the four salts in the current study showed that the compounds of Example 7 were obviously superior in pharmacokinetics.

5 En resumen, la preparacion de los compuestos de la presente divulgacion era sencilla y tenia buen rendimiento. Especialmente, las sales etanolamina, sales colina, sales dietilamina y sales piperazina tenian superioridad en el proceso de sintesis ya que pueden cristalizar directamente. En comparacion con los acidos libres, la solubilidad de las sales de la presente divulgacion obviamente aumento en los disolventes convencionales. Las sales etanolamina 5 In summary, the preparation of the compounds of the present disclosure was simple and had good performance. Especially, ethanolamine salts, choline salts, diethylamine salts and piperazine salts had superiority in the synthesis process since they can crystallize directly. In comparison with free acids, the solubility of the salts of the present disclosure obviously increased in conventional solvents. Ethanolamine salts

10 eran menos higroscopicas y eran adecuadas para preparar una formulacion convencional y facil de conservar. La bioactividad de las sales de la presente divulgacion obviamente mejoro. La farmacocinetica obviamente tambien mejoro en las ratas y beagles y tuvo mejores caracteristicas farmacocineticas, especialmente las sales etanolamina. 10 were less hygroscopic and were suitable for preparing a conventional and easy to preserve formulation. The bioactivity of the salts of the present disclosure obviously improved. Pharmacokinetics obviously also improved in rats and beagles and had better pharmacokinetic characteristics, especially ethanolamine salts.

Claims (14)

REIVINDICACIONES 1. Sales farmaceuticamente aceptables de un compuesto que tiene formula (I): 1. Pharmaceutically acceptable salts of a compound having formula (I): 5 en la que: 5 in which: Het se selecciona entre el grupo que consiste en fenilo, furilo y tienilo; cada uno de R1, R2, R3 y R4 se selecciona independientemente entre el grupo que consiste en hidrogeno y alquilo; Het is selected from the group consisting of phenyl, furyl and thienyl; each of R1, R2, R3 and R4 is independently selected from the group consisting of hydrogen and I rent; 10 n es 0, 1 o 2; y las sales son sales de adicion de bases que se seleccionan entre el grupo que consiste en sal sodica, sal de litio, sal potasica, sal calcica, sal de magnesio, sal de arginina, sal de lisina, sal de metanamina, sal de dimetilamina, sal de trimetilamina, sal de etilamina, sal de dietilamina, sal de trietilamina, sal de etanolamina, sal de piperazina, sal de dibencil etilendiamina, sal de meglumina, sal de trometamina, sal de 10 n is 0, 1 or 2; and the salts are base addition salts that are selected from the group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, methanamine salt, dimethylamine salt , trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzyl ethylenediamine salt, meglumine salt, tromethamine salt, salt 15 tetrametil amonio cuaternario, sal de tetraetil amonio cuaternario y sal colina. Quaternary tetramethyl ammonium, quaternary tetraethyl ammonium salt and choline salt. 2. Las sales farmaceuticamente aceptables de acuerdo con la reivindicacion 1, en las que las sales se seleccionan entre el grupo que consiste en sal de dietilamina, sal de etanolamina, sal colina, sal de piperazina, sal de meglumina y sal de trometamina, preferiblemente sal de etanolamina, sal colina, sal de meglumina y sal de 2. The pharmaceutically acceptable salts according to claim 1, wherein the salts are selected from the group consisting of diethylamine salt, ethanolamine salt, choline salt, piperazine salt, meglumine salt and tromethamine salt, preferably ethanolamine salt, choline salt, meglumine salt and salt 20 trometamina, y mucho mas preferiblemente sal de etanolamina. 20 tromethamine, and much more preferably ethanolamine salt. 3. Las sales farmaceuticamente aceptables de acuerdo con la reivindicacion 1, en las que n es 2. 3. Pharmaceutically acceptable salts according to claim 1, wherein n is 2. 4. Las sales farmaceuticamente aceptables de acuerdo con una cualquiera de las reivindicaciones 1-3, 25 en las que las sales se seleccionan entre el grupo que consiste en: 5. Proceso para preparar las sales farmaceuticamente aceptables de acuerdo con una cualquiera de las reivindicaciones 1-4, que comprende las etapas de: 4. Pharmaceutically acceptable salts according to any one of claims 1-3, wherein the salts are selected from the group consisting of: 5. Process for preparing pharmaceutically acceptable salts according to any one of claims 1-4, which includes the stages of: (a) disolver o suspender el compuesto que tiene la formula (I) en un disolvente organico, donde el disolvente organico se selecciona entre el grupo que consiste en metanol, etanol, acetona, acetato de etilo y (a) dissolve or suspend the compound having the formula (I) in an organic solvent, where the organic solvent is selected from the group consisting of methanol, ethanol, acetone, ethyl acetate and tetrahidrofurano, preferiblemente tetrahidrofurano; tetrahydrofuran, preferably tetrahydrofuran;
(b)(b)
afadir una base a la mezcla con agitacion;  add a base to the mixture with stirring;
(c)(C)
obtener las sales farmaceuticamente aceptables del compuesto que tiene la formula (1).  obtain the pharmaceutically acceptable salts of the compound having the formula (1).
6. 6.
El proceso de acuerdo con la reivindicacion 5, en el que la base se selecciona entre el grupo que consiste en hidroxido sodico, hidroxido de litio, hidroxido potasico, hidroxido de calcio, hidroxido de magnesio, lisina, arginina, metanamina, dimetilamina, trimetilamina, etilamina, dietilamina, trietilamina, etanolamina, piperazina, dibencil etilendiamina, meglumina, trometamina, tetrametil amonio cuaternario, tetraetil amonio cuaternario e hidroxido de colina, preferiblemente dietilamina, etanolamina, hidroxido de colina, piperazina, meglumina y trometamina, mas preferiblemente etanolamina, hidroxido de colina, meglumina y trometamina, y mucho mas preferiblemente etanolamina. The process according to claim 5, wherein the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lysine, arginine, methanamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzyl ethylenediamine, meglumine, tromethamine, tetramethyl quaternary ammonium, tetraethyl ammonium quaternary and choline hydroxide, preferably diethylamine, ethanolamine, choline hydroxide, piperazine, meglumine and tromethamine, more preferably choline, meglumine and tromethamine, and much more preferably ethanolamine.
7. 7.
El proceso de acuerdo con la reivindicacion 5 o la reivindicacion 6, en el que la proporcion de equivalencia del compuesto que tiene la formula (I) y la base es 1:5-5:1, preferiblemente 1:1-1:3, y mas preferiblemente 1:1-1:2. The process according to claim 5 or claim 6, wherein the equivalence ratio of the compound having the formula (I) and the base is 1: 5-5: 1, preferably 1: 1-1: 3, and more preferably 1: 1-1: 2.
8. 8.
Composicion farmaceutica que comprende una cantidad terapeuticamente eficaz de las sales farmaceuticamente aceptables de acuerdo con una cualquiera de las reivindicaciones 1-4 y vehiculos y agentes diluyentes farmaceuticamente aceptables. Pharmaceutical composition comprising a therapeutically effective amount of the pharmaceutically acceptable salts according to any one of claims 1-4 and pharmaceutically acceptable carriers and diluting agents.
9. 9.
La composicion farmaceutica de acuerdo con la reivindicacion 8, en la que la composicion se coadministra con una cantidad terapeuticamente eficaz de un farmaco seleccionado entre el grupo que consiste en un factor estimulador de colonias, una citocina, una quimiocina, una interleucina y un agonista del receptor de citocina. The pharmaceutical composition according to claim 8, wherein the composition is co-administered with a therapeutically effective amount of a drug selected from the group consisting of a colony stimulating factor, a cytokine, a chemokine, an interleukin and an agonist of the cytokine receptor
10. 10.
Proceso para preparar la composicion de acuerdo con la reivindicacion 8, que comprende la etapa de combinar el compuesto de la reivindicacion 1 con los vehiculos o agentes diluyentes farmaceuticamente aceptables. Process for preparing the composition according to claim 8, which comprises the step of combining the compound of claim 1 with the pharmaceutically acceptable carrier or diluting agents.
11. eleven.
Uso de las sales farmaceuticamente aceptables del compuesto que tienen la formula (I) de acuerdo con una cualquiera de las reivindicaciones 1-4 en la preparacion de un agonista del receptor de trombopoyetina. Use of the pharmaceutically acceptable salts of the compound having the formula (I) according to any one of claims 1-4 in the preparation of a thrombopoietin receptor agonist.
12. 12.
Sales farmaceuticamente aceptables del compuesto que tiene la formula (I) de acuerdo con una cualquiera de las reivindicaciones 1-4 para su uso como un medicamento para el tratamiento de la trombocitopenia. Pharmaceutically acceptable salts of the compound having formula (I) according to any one of claims 1-4 for use as a medicament for the treatment of thrombocytopenia.
13. 13.
Las sales farmaceuticamente aceptables de acuerdo con la reivindicacion 12, en las que el medicamento se co-administra con un farmaco seleccionado entre el grupo que consiste en un factor estimulador de colonias, una citocina, una quimiocina, una interleucina o agonista o antagonista del receptor de citocina, un receptor soluble, un anticuerpo agonista o antagonista de receptor, o uno o mas peptidos o compuestos de moleculas pequefas que tienen el mismo mecanismo con el farmaco. Pharmaceutically acceptable salts according to claim 12, wherein the medicament is co-administered with a drug selected from the group consisting of a colony stimulating factor, a cytokine, a chemokine, an interleukin or agonist or receptor antagonist of cytokine, a soluble receptor, an agonist antibody or receptor antagonist, or one or more peptides or small molecule compounds that have the same mechanism with the drug.
14. 14.
Las sales farmaceuticamente aceptables de acuerdo con la reivindicacion 12, en las que el medicamento esta en forma de forma de dosificacion oral. The pharmaceutically acceptable salts according to claim 12, wherein the medicament is in oral dosage form.
15. fifteen.
Las sales farmaceuticamente aceptables de acuerdo con la reivindicacion 12, en las que el medicamento esta en forma de forma de dosificacion parenteral. Pharmaceutically acceptable salts according to claim 12, wherein the medicament is in parenteral dosage form.
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